4-Ring imidazole derivatives as modulators of metabotropic glutamate receptor-5

ABSTRACT

Imidazole compounds of Formula (I): (where A, B, R 11 , R 12 , W, X, Y and Z are as defined herein) wherein the imidazole is substituted directly, or by a bridge, with i) a heteroaryl moiety containing N adjacent to the point of connection of the heteroaryl and ii) another heteroaryl or aryl ring, with at least one of the rings being further substituted with another ring, which are MgluR5 modulators useful in the treatment of psychiatric and mood disorders such as, for example, schizophrenia, anxiety, depression, bipolar disorders, and panic, as well as in the treatment of pain, Parkinson&#39;s disease, cognitive dysfunction, epilepsy, circadian rhythm and sleep disorders—such as shift-work induced sleep disorder and jet-lag, drug addiction, drug abuse, drug withdrawal, obesity and other diseases, and pharmaceutical compositions and methods of treating these diseases.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention is directed to imidazole compounds substitutedwith i) a heteroaryl ring and ii) another heteroaryl or aryl ring withat leastone of the rings being further substituted with another ring. Inparticular, this invention is directed to imidazole compoundssubstituted directly, or by a bridge, with i) a heteroaryl moietycontaining N adjacent to the point of connection of the heteroaryl andii) another heteroaryl or aryl ring, with at least one of the ringsbeing further substituted with another ring, which are metabotropicglutamate receptor—subtype 5 (“mGluR5”) modulators useful in thetreatment of psychiatric and mood disorders such as, for example,schizophrenia, anxiety, depression, panic, bipolar disorder, andcircadian rhythm disorders, as well as in the treatment of pain,Parkinson's disease, cognitive dysfunction, epilepsy, drug addiction,drug abuse, drug withdrawal, obesity and other diseases.

2. Related Background

A major excitatory neurotransmitter in the mammalian nervous system isthe glutamate molecule, which binds to neurons, thereby activating cellsurface receptors. Such surface receptors are characterized as eitherionotropic or metabotropic glutamate receptors. The metabotropicglutamate receptors (“mGluR”) are G protein-coupled receptors thatactivate intracellular second messenger systems when bound to glutamate.Activation of mGluR results in a variety of cellular responses. Inparticular, mGluR1 and mGluR5 activate phospholipase C, which isfollowed by mobilizing intracellular calcium.

Modulation of metabotropic glutamate receptor subtype 5 (mGluR5) isuseful in the treatment of diseases that affect the nervous system (seefor example W. P. J. M Spooren et al., Trends Pharmacol. Sci., 22:331-337 (2001) and references cited therein). For example, recentevidence demonstrates the involvement of mGluR5 in nociceptive processesand that modulation of mGluR5 using mGluR5-selective compounds is usefulin the treatment of various pain states, including acute, persistent andchronic pain [K Walker et al., Neuropharmacology, 40: 1-9 (2001); F.Bordi, A. Ugolini Brain Res., 871: 223-233 (2001)], inflammatory pain [KWalker et al., Neuropharmacology, 40: 10-19 (2001); Bhave et al. NatureNeurosci. 4: 417-423 (2001)] and neuropathic pain [Dogrul et al.Neurosci. Lett. 292: 115-118 (2000)).

Further evidence supports the use of modulators of mGluR5 in thetreatment of psychiatric and neurological disorders. For example,mGluR5-selective compounds such as 2-methyl-6-(phenylethynyl)-pyridine(“MPEP”) are effective in animal models of mood disorders, includinganxiety and depression [W. P. J. M Spooren et al., J. Pharmacol. Exp.Ther., 295: 1267-1275 (2000); E. Tatarczynska et al, Brit. J.Pharmacol., 132: 1423-1430 (2001); A. Klodzynska et al, Pol. J.Pharmacol., 132: 1423-1430 (2001)). Gene expression data from humansindicate that modulation of mGluR5 may be useful for the treatment ofschizophrenia [T. Ohnuma et al, Mol. Brain. Res., 56: 207-217 (1998);ibid, Mol. Brain. Res., 85: 24-31 (2000)]. Studies have also shown arole for mGluR5, and the potential utility of mGluR5-modulatorycompounds, in the treatment of movement disorders such as Parkinson'sdisease [W. P. J. M Spooren et al., Europ. J. Pharmamcol. 406: 403-410(2000); H. Awad et al., J. Neurosci. 20: 7871-7879 (2000); K. Ossawa etal. Neuropharmacol. 41: 413-420 (2001)]. Other research supports a rolefor mGluR5 modulation in the treatment of cognitive dysfunction [G.Riedel et al, Neuropharmacol. 39: 1943-1951 (2000)], epilepsy [A.Chapman et al, Neuropharmacol. 39:1567-1574 (2000)] and neuroprotection[V. Bruno et al, Neuropharmacol. 39: 2223-2230 (2000)]. Studies withmGluR5 knockout mice and MPEP also suggest that modulation of thesereceptors may be useful in the treatment of drug addiction, drug abuseand drug withdrawal [C. Chiamulera et al. Nature Neurosci. 4: 873-874(2001)].

International Patent Publications WO 01/12627 and WO 99/26927 describeheteropolycyclic compounds and their use as metabotropic glutamatereceptor antagonists.

U.S. Pat. No. 3,647,809 describes pyridyl-1,2,4-oxadiazole derivatives.U.S. Pat. No.4,022,901 describes 3-pyridyl-5-isothiocyanophenyloxadiazoles. International Patent Publication WO 98/17652 describesoxadiazoles, WO 97/03967 describes various substituted aromaticcompounds, JP 13233767A and WO 94/22846 describe various heterocycliccompounds.

Compounds that include ringed systems are described by variousinvestigators as effective for a variety of therapies and utilities. Forexample, International Patent Publication No. WO 98/25883 describesketobenzamides as calpain inhibitors, European Patent Publication No. EP811610 and U.S. Pat. Nos. 5,679,712, 5,693,672 and 5,747,541describesubstituted benzoylguanidine sodium channel blockers, and U.S. Pat. No.5,736,297 describes ring systems useful as a photosensitive composition.

However, there remains a need for novel compounds and compositions thattherapeutically inhibit mGluR5 with minimal side effects.

SUMMARY OF THE INVENTION

The present invention is directed to novel imidazole compounds such asthose of Formula (I):

(where A, B, R₁₁, R₁₂, W, X, Y and Z are as defined herein) wherein theimidazole is substituted directly, or by a bridge, with i) a heteroarylmoiety containing N adjacent to the point of connection of theheteroaryl and ii) another heteroaryl or aryl ring, with at least one ofthe rings being further substituted with another ring, which aremetabotropic glutamate receptor—subtype 5 modulators useful in thetreatment of psychiatric and mood disorders such as, for example,schizophrenia, anxiety, depression, bipolar disorders, and panic, aswell as in the treatment of pain, Parkinson's disease, cognitivedysfunction, epilepsy, circadian rhythm and sleep disorders—such asshift-work induced sleep disorder and jet-lag, drug addiction, drugabuse, drug withdrawal, obesity and other diseases. This invention alsoprovides a pharmaceutical composition which includes an effective amountof the novel imidazole compounds substituted with a heteroaryl moiety,and a pharmaceutically acceptable carrier.

This invention further provides a method of treatment of psychiatric andmood disorders such as, for example, schizophrenia, anxiety, depression,panic, bipolar disorders, and circadian rhythm and sleep disorders, aswell as a method of treatment of pain, Parkinson's disease, cognitivedysfunction, epilepsy, obesity, drug addiction, drug abuse and drugwithdrawal by the administration of an effective amount of the novelimidazole compounds substituted with a heteroaryl moiety.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of the present invention are represented by Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

X and Y each independently is aryl or heteroaryl wherein at least one ofX and Y is a heteroaryl with N adjacent to the position of attachment toA or B respectively;

X is optionally substituted with 1-7 independent halogen, —CN, NO₂,—C₁₋₆alkyl, —C₁₋₆alkenyl, —C₁₋₆alkynyl, —OR¹, —NR¹R², —C(═NR¹)NR²R³,—N(═NR¹)NR²R³, —N(═NR¹)NR²R³, —NR¹COR², —NR¹CO₂R², —NR¹SO₂R⁴,—NR¹CONR²R³, —SR⁴, —SOR⁴, —SO₂R⁴, —SO_(NR) ¹R², —COR¹, —CO₂R¹, —CONR¹R²,—C(═NR¹)R², or —C(═NOR¹)R² substituents, wherein optionally twosubstituents are combined to form a cycloalkyl or heterocycloalkyl ringfused to X; wherein the —C₁₋₆alkyl substituent, cycloalkyl ring, orheterocycloalkyl ring each optionally is further substituted with 1-5independent halogen, —CN, —C₁₋₆alkyl, —O(C₀₋₆alkyl), —(C₃₋₇cycloalkyl),—O(aryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl), —N(C₀₋₆alkyl)(C₃₋₇cycloalkyl), or—N(C₀₋₆alkyl)(aryl) groups;

R¹, R², and R³ each independently is —C₀₋₆alkyl, —C₃₋₇cycloalkyl,heteroaryl, or aryl; any of which is optionally substituted with 1-5independent halogen, —CN, —C₁₋₆alkyl, —O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl),—O(aryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl), —N(C₀₋₆alkyl)(C₃₋₇cycloalkyl),—N(C₀₋₆alkyl)(aryl) substituents;

R⁴ is —C₁₋₆alkyl, —C₃₋₇cycloalkyl, heteroaryl, or aryl; optionallysubstituted with 1-5 independent halogen, —CN, —C₁₋₆alkyl,—O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl), —O(aryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl),—N(C₀₋₆alkyl)(C₃₋₇cycloalkyl), —N(C₀₋₆alkyl)(aryl) substituents;

A is —C₀₋₄alkyl, —C₀₋₂alkyl-SO—C₀₋₂alkyl-, —C₀₋₂alkyl-SO₂—C₀₋₂alkyl-,—C₀₋₂alkyl-CO—C₀₋₂alkyl-, —C₀₋₂alkyl-NR⁹CO—C₀₋₂alkyl-,—C₀₋₂alkyl-NR⁹SO₂—C₀₋₂alkyl- or -heteroC₀₋₄alkyl;

W is —C₃₋₇cycloalkyl, -heteroC₃₋₇cycloalkyl, —C₀₋₆alkylaryl, or—C₀₋₆alkylheteroaryl optionally substituted with 1-7 independenthalogen, —CN, NO₂, —C₁₋₆alkyl, —C₁₋₆alkenyl, —C₁₋₆alkynyl, —OR¹, —NR¹R²,—C(═NR¹)NR²R³, —N(═NR¹)NR²R³, —NR¹COR², —NR¹CO₂R², —NR¹SO₂R⁴,—NR¹CONR²R³, —SR⁴, —SOR⁴, —SO₂R⁴, —SO₂NR¹R², —COR¹, —CO₂R¹, —CONR¹R²,—C(═NR¹)R², or —C(═NOR¹)R² substituents;

Y is optionally substituted with 1-7 independent halogen, —CN, NO₂,—C₁₋₆alkyl, —C₁₋₆alkenyl, —C₁₋₆alkynyl, —OR⁵, —NR⁵R⁶, —C(═NR⁵)NR⁶R⁷,—NR⁵)NR⁶R⁷, —NR⁵COR⁶, —NR⁵CO₂R⁶, —NR⁵SO₂R⁸, —NR⁵CONR⁶R⁷, —SR⁸, —SOR⁸,—SO₂R⁸, —SO₂NR⁵R⁶, —COR⁵, —CO₂R⁵, —CONR⁵R⁶, —C(═NR⁵)R⁶, or —C(═NOR⁵)R⁶substituents, wherein optionally two substituents are combined to form acycloalkyl or heterocycloalkyl ring fused to Y; wherein the —C₁₋₆alkylsubstituent, cycloalkyl ring, or heterocycloalkyl ring each optionallyis further substituted with 1-5 independent halogen, —CN, —C₁₋₆alkyl,—O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl), —O(aryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl),—N(C₀₋₆alkyl)(C₃₋₇cycloalkyl), or —N(C₀₋₆alkyl)(aryl) groups;

R⁵, R⁶, and R⁷ each independently is —C₀₋₆alkyl, —C₃₋₇cycloalkyl,heteroaryl, or aryl; any of which is optionally substituted with 1-5independent halogen, —CN, —C₁₋₆alkyl, —O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl),—O(aryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl), —N(C₀₋₆alkyl)(C₃₋₇cycloalkyl),—N(C₀₋₆alkyl)(aryl) substituents;

R⁸ is —C₁₋₆alkyl, —C₃₋₇cycloalkyl, heteroaryl, or aryl; optionallysubstituted with 1-5 independent halogen, —CN, —C₁₋₆alkyl,—O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl), —O(aryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl),—N(C₀₋₆alkyl)(C₃₋₇cycloalkyl), —N(C₀₋₆alkyl)(aryl) substituents;

B is —C₀₋₄alkyl, —C₀₋₂alkyl-SO—C₀₋₂alkyl-, —C₀₋₂alkyl-SO₂—C₀₋₂alkyl-,—C₀₋₂alkyl-CO—C₀₋₂alkyl-, —C₀₋₂alkyl-NR¹⁰CO—C₀₋₂alkyl-,—C₀₋₂alkyl-NR¹⁰SO₂—C₀₋₂alkyl- or -heteroC₀₋₄alkyl;

R⁹ and R¹⁰ each independently is —C₀₋₆alkyl, —C₃₋₇cycloalkyl,heteroaryl, or aryl; any of which is optionally substituted with 1-5independent halogen, —CN, —C₁₋₆alkyl, —O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl),—O(aryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl), —N(C₀₋₆alkyl)(C₃₋₇cycloalkyl),—N(C₀₋₆alkyl)(aryl) substituents;

Z is —C₃₋₇cycloalkyl, -heteroC₃₋₇cycloalkyl, —C₀₋₆alkylaryl, or—C₀₋₆alkylheteroaryl optionally substituted with 1-7 independenthalogen, —CN, NO₂, —C₁₋₆alkyl, —C₁₋₆alkenyl, —C₁₋₆alkynyl, —OR¹, —NR¹R²,—C(═NR¹)NR²R³, —N(═NR¹)NR²R³, —NR¹COR², —NR¹CO₂R², —NR¹SO₂R⁴,—NR¹CONR²R³, —SR⁴, —SOR⁴, —SO₂R⁴, —SO₂NR¹R², —COR¹, —CO₂R¹, —CONR¹R²,—C(═NR¹)R², or —C(═NOR¹)R² substituents;

one of W and Z is optionally absent;

R¹¹ and R¹² is each independently halogen, —C₀₋₆alkyl, —C₀₋₆alkoxyl, ═O,═N(C₀₋₄alkyl),or —N(C₀₋₄alkyl)(C₀₋₄alkyl);

any alkyl optionally substituted with 1-5 independent halogensubstituents, and any N may be an N-oxide.

In one aspect, the compounds of this invention are represented byFormula (1) or a pharmaceutically acceptable salt thereof, wherein:

X is 2-pyridyl optionally substituted with 1-4 independent halogen, —CN,NO₂, —C₁₋₆alkyl, —C₁₋₆alkenyl, —C₁₋₆alkynyl, —OR¹, —NR¹R²,—C(═NR¹)NR²R³, —N(═NR¹)NR²R³, —NR¹COR², —NR¹CO₂R², —NR¹SO₂R⁴,—NR¹CONR²R³, —SR⁴, —SOR⁴, —SO₂R⁴, —SO₂NR¹R², —COR¹, —CO₂R¹, —CONR¹R²,—C(═NR¹)R², or —C(═NOR¹)R² substituents, wherein optionally twosubstituents are combined to form a cycloalkyl or heterocycloalkyl ringfused to X; wherein the —C₁₋₆alkyl substituent, cycloalkyl ring, orheterocycloalkyl ring each optionally is further substituted with 1-5independent halogen, —CN, —C₁₋₆alkyl, —O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl),—O(aryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl), —N(C₀₋₆alkyl)(C₃₋₇cycloalkyl), or—N(C₀₋₆alkyl)(aryl) groups;

R¹, R², and R³ each independently is —C₀₋₆alkyl, —C₃₋₇cycloalkyl,heteroaryl, or aryl; any of which is optionally substituted with 1-5independent halogen, —CN, —C₁₋₆alkyl, —O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl),—O(aryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl), —N(C₀₋₆alkyl)(C₃₋₇cycloalkyl),—N(C₀₋₆alkyl)(aryl) substituents;

R⁴ is —C₁₋₆alkyl, —C₃₋₇cycloalkyl, heteroaryl, or aryl; optionallysubstituted with 1-5 independent halogen, —CN, —C₁₋₆alkyl,—O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl), —O(aryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl),—N(C₀₋₆alkyl)(C₃₋₇cycloalkyl), —N(C₀₋₆alkyl)(aryl) substituents;

A is —C₀₋₄alkyl, —C₀₋₂alkyl-SO—C₀₋₂alkyl-, —C₀₋₂alkyl-SO₂—C₀₋₂alkyl-,—C₀₋₂alkyl-CO—C₀₋₂alkyl-, —C₀₋₂alkyl-NR⁹CO—C₀₋₂alkyl-,—C₀₋₂alkyl-NR⁹SO₂—C₀₋₂alkyl- or —heteroC₀₋₄alkyl;

W is —C₃₋₇cycloalkyl, -heteroC₃₋₇cycloalkyl, —C₀₋₆alkylaryl, or—C₀₋₆alkylheteroaryl optionally substituted with 1-7 independenthalogen, —CN, NO₂, —C₁₋₆alkyl, —C₁₋₆alkenyl, —C₁₋₆alkynyl, —OR¹, —NR¹R²,—C(═NR¹)NR²R³, —N(═NR¹)NR²R³, —NR¹COR², —NR¹CO₂R², —NR¹SO₂R⁴,—NR¹CONR²R³, —SR⁴, —SOR⁴, —SO₂R⁴, —SO₂NR¹R², —COR¹, —CO₂R¹, —CONR¹R²,—C(═NR¹)R², or —C(═NOR¹)R² substituents;

Y is aryl or heteroaryl optionally substituted with 1-7 independenthalogen, —CN, NO₂, —C₁₋₆alkyl, —C₁₋₆alkenyl, —C₁₋₆alkynyl, —OR⁵, —NR⁵R⁶,—C(═NR⁵)NR⁶R⁷, —N(═NR⁵)NR⁶R⁷, —NR⁵COR⁶, —NR⁵CO₂R⁶, —NR⁵SO₂R⁸,—NR⁵CONR⁶R⁷, —SR⁸, —SOR$⁸, —SO₂R⁸, —SO₂NR⁵R⁶, —COR⁵, —CO₂R⁵, —CONR⁵R⁶,—C(═NR⁵)R⁶, or —C(═NOR⁵)R⁶ substituents, wherein optionally twosubstituents are combined to form a cycloalkyl or heterocycloalkyl ringfused to Y; wherein the —C₁₋₆alkyl substituent, cycloalkyl ring, orheterocycloalkyl ring each optionally is further substituted with 1-5independent halogen, —CN, —C₁₋₆alkyl, —O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl),—O(aryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl), —N(C₀₋₆alkyl)(C₃₋₇cycloalkyl), or—N(C₀₋₆alkyl)(aryl) groups;

R⁵, R⁶, and R⁷ each independently is —C₀₋₆alkyl, —C₃₋₇cycloalkyl,heteroaryl, or aryl; any of which is optionally substituted with 1-5independent halogen, —CN, —C₁₋₆alkyl, —O(C₀₋₆alkyl), —(C₃₋₇cycloalkyl),—O(aryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl), —N(C₀₋₆alkyl)(C₃₋₇cycloalkyl),—N(C₀₋₆alkyl)(aryl) substituents;

R⁸ is —C₁₋₆alkyl, —C₃₋₇cycloalkyl, heteroaryl, or aryl; optionallysubstituted with 1-5 independent halogen, —CN, —C₁₋₆alkyl,—O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl), —O(aryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl),—N(C₀₋₆alkyl)(C₃₋₇cycloalkyl), —N(C₀₋₆alkyl)(aryl) substituents;

B is —C₀₋₄alkyl, —C₀₋₂alkyl-SO—C₀₋₂alkyl-, —C₀₋₂alkyl-SO₂—C₀₋₂alkyl-,—C₀₋₂alkyl-CO—C₀₋₂alkyl-, —C₀₋₂alkyl-NR¹⁰CO—C₀₋₂alkyl-,—C₀₋₂alkyl-NR¹⁰SO₂—C₀₋₂alkyl- or -heteroC₀₋₄alkyl;

R⁹ and R¹⁰ each independently is —C₀₋₆alkyl, —C₃₋₇cycloalkyl,heteroaryl, or aryl; any of which is optionally substituted with 1-5independent halogen, —CN, —C₁₋₆alkyl, —O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl),—O(aryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl), —N(C₀₋₆alkyl)(C₃₋₇cycloalkyl),—N(C₀₋₆alkyl)(aryl) substituents;

Z is —C₃₋₇cycloalkyl, -heteroC₃₋₇cycloalkyl, —C₀₋₆alkylaryl, or—C₀₋₆alkylheteroaryl optionally substituted with 1-7 independenthalogen, —CN, NO₂, —C₁₋₆alkyl, —C₁₋₆alkenyl, —C₁₋₆alkynyl, —OR¹, —NR¹R²,—C(═NR¹)NR²R³, —N(═NR¹)NR²R³, —NR¹COR², —NR¹CO₂R², —NR¹SO₂R⁴,—NR¹CONR²R³, —SR⁴, —SOR⁴, —SO₂R⁴, —SO₂NR¹R², —COR¹, —C₀₋₂R¹, —CONR¹R²,—C(═NR¹)R², or —C(═NOR¹)R² substituents;

one of W and Z is optionally absent;

R¹¹ and R¹² is each independently halogen, —C₀₋₆alkyl, —C₀₋₆alkoxyl, ═O,═N(C₀₋₄alkyl),or —N(C₀₋₄alkyl)(C₀₋₄alkyl); and

any alkyl optionally substituted with 1-5 independent halogensubstituents, and any N may be an N-oxide.

In an embodiment of this one aspect, the compounds of this invention arerepresented by Formula (1) or a pharmaceutically acceptable saltthereof, wherein:

X is 2-pyridyl optionally substituted with 1-4 independent halogen, —CN,NO₂, —C₁₋₆alkyl, —C₁₋₆alkenyl, —C₁₋₆alkynyl, —OR¹, —NR¹R²,—C(═NR¹)NR²R₃, —N(═NR¹)NR²R³, —NR¹COR², —NR¹CO₂R², —NR¹SO₂R⁴,—NR¹CONR²R³, —SR⁴, —SOR⁴, —SO₂NR¹R², —COR¹, —CO₂R¹, —CONR¹R²,—C(═NR¹)R², or —C(═NOR¹)R² substituents, wherein optionally twosubstituents are combined to form a cycloalkyl or heterocycloalkyl ringfused to X; wherein the —C₁₋₆alkyl substituent, cycloalkyl ring, orheterocycloalkyl ring each optionally is further substituted with 1-5independent halogen, —CN, —C₁₋₆alkyl, —O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl),—O(aryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl), —N(C₀₋₆alkyl)(C₃₋₇cycloalkyl), or—N(C₀₋₆alkyl)(aryl) groups;

R¹, R², and R³ each independently is —C₀₋₆alkyl, —C₃₋₇cycloalkyl,heteroaryl, or aryl; any of which is optionally substituted with 1-5independent halogen, —CN, —C₁₋₆alkyl, —O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl),—O(aryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl), —N(C₀₋₆alkyl)(C₃₋₇cycloalkyl),—N(C₀₋₆alkyl)(aryl) substituents;

R⁴ is —C₁₋₆alkyl, —C₃₋₇cycloalkyl, heteroaryl, or aryl; optionallysubstituted with 1-5 independent halogen, —CN, —C₁₋₆alkyl,—O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl), —O(aryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl),—N(C₀₋₆alkyl)(C₃₋₇cycloalkyl), —N(C₀₋₆alkyl)(aryl) substituents;

A is —(C₀₋₄alkyl, —C₀₋₂alkyl-SO—C₀₋₂alkyl-, —C₀₋₂alkyl-SO₂—C₀₋₂alkyl-,—C₀₋₂alkyl-CO—C₀₋₂alkyl-, —C₀₋₂alkyl-NR⁹CO—C₀₋₂alkyl-,—C₂alkyl-NR⁹SO₂—C₂alkyl- or heteroC₀₋₄alkyl;

W is —C₃₋₇cycloalkyl, -heteroC₃₋₇cycloalkyl, —C₀₋₆alkylaryl, or—C₀₋₆alkylheteroaryl optionally substituted with 1-7 independenthalogen, —CN, NO₂, —C₁₋₆alkyl, —C₁₋₆alkenyl, —C₁₋₆alkynyl, —OR¹, —NR¹R²,—C(═NR¹)NR²R³, —N(═NR¹)NR²R³, —NR¹COR², —NR¹CO₂R², —NR¹SO₂R⁴,—NR¹CONR²R³, —SR⁴, —SOR⁴, —SO₂R⁴, —SO₂NR¹R², —COR¹, —CO₂R¹, —CONR¹R²,—C(═NR¹)R², or —C(═NOR¹)R² substituents;

Y is phenyl optionally substituted with 1-5 independent halogen, —CN,NO₂, —C₁₋₆alkyl, —C₁₋₆alkenyl, —C₁₋₆alkynyl, —OR⁵, —NR⁵R⁶,—C(═NR⁵)NR⁶R⁷, —N(═NR⁵)NR⁶R⁷, —NR⁵COR⁶, —NR⁵CO₂R⁶, —NR⁵SO₂R⁸,—NR₅CONR⁶R⁷, —SR⁸, —SOR⁸, —SO₂R⁸, —SO₂NR⁵R⁶, —COR⁵, —CO₂R⁵, —CONR⁵R⁶,—C(═NR⁵)R⁶, or —C(═NOR⁵)R⁶ substituents, wherein two substituents arecombined to form a cycloalkyl or heterocycloalkyl ring fused to Y;wherein the —C₁₋₆alkyl substituent, cycloalkyl ring, or heterocycloalkylring each optionally is further substituted with 1-5 independenthalogen, —CN, —C₁₋₆alkyl, —O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl), —O(aryl),—N(C₀₋₆alkyl)(C₀₋₆alkyl), —N(C₀₋₆alkyl)(C₃₋₇cycloalkyl), or—N(C₀₋₆alkyl)(aryl) groups;

R⁵, R⁶, and R⁷ each independently is —C₀₋₆alkyl, —C₃₋₇cycloalkyl,heteroaryl, or aryl; any of which is optionally substituted with 1-5independent halogen, —CN, —C₁₋₆alkyl, —O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl),—O(aryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl), —N(C₀₋₆alkyl)(C₃₋₇cycloalkyl),—N(C₀₋₆alkyl)(aryl) substituents;

R⁸ is —C₁₋₆alkyl, —C₃₋₇cycloalkyl, heteroaryl, or aryl; optionallysubstituted with 1-5 independent halogen, —CN, —C₁₋₆alkyl,—O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl), —O(aryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl),—N(C₀₋₆alkyl)(C₃₋₇cycloalkyl), —N(C₀₋₆alkyl)(aryl) substituents;

B is —(C₀₋₄alkyl, —C₀₋₂alkyl-SO—C₀₋₂alkyl-, —C₀₋₂alkyl-SO₂—C₀₋₂alkyl-,—C₀₋₂alkyl-CO—C₀₋₂alkyl-, —C₀₋₂alkyl-NR¹⁰CO—C₀₋₂alkyl-,—C₀₋₂alkyl-NR¹⁰SO₂—C₀₋₂alkyl- or -heteroC₀₋₄alkyl;

R⁹ and R¹⁰ each independently is —C₀₋₆alkyl, —C₃₋₇cycloalkyl,heteroaryl, or aryl; any of which is optionally substituted with 1-5independent halogen, —CN, —C₁₋₆alkyl, —O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl),—O(aryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl), —N(C₀₋₆alkyl)(C₃₋₇cycloalkyl),—N(C₀₋₆alkyl)(aryl) substituents;

Z is —C₃₋₇cycloalkyl, -heteroC₃₋₇cycloalkyl, —C₀₋₆alkylaryl, or—C₀₋₆alkylheteroaryl optionally substituted with 1-7 independenthalogen, —CN, NO₂, —C₁₋₆alkyl, —C₁₋₆alkenyl, —C₁₋₆alkynyl, —OR¹, —NR¹R²,—C(═NR¹)NR²R³, —N(═NR¹)NR²R³, —NR¹COR², —NR¹CO₂R², —NR¹SO₂R⁴,—NR¹CONR²R³, —SR⁴, —SOR⁴, —SO₂R⁴, —SO₂NR¹R², —COR¹, —CO₂R¹, —CONR¹R²,—C(═NR¹)R², or —C(═NOR¹)R² substituents;

one of W and Z is optionally absent;

R¹¹ and R¹² is each independently halogen, —C₀₋₆alkyl, —C₀₋₆alkoxyl, ═O,═N(C₀₋₄alkyl),or —N(C₀₋₄alkyl)(C₀₋₄alkyl); and

any alkyl optionally substituted with 1-5 independent halogensubstituents, and any N may be an N-oxide.

In a second aspect, the compounds of this invention are represented byFormula (I) or a pharmaceutically acceptable salt thereof, wherein:

X is aryl or heteroaryl optionally substituted with 1-7 independenthalogen, —CN, NO₂, —C₁₋₆alkyl, —C₁₋₆alkenyl, —C₁₋₆alkynyl, —OR¹, —NR¹R²,—C(═NR¹)NR²R³, —N(═NR¹)NR²R³, —NR¹COR², —NR¹CO₂R², —NR¹SO₂R⁴,—NR¹CONR²R³, —SR⁴, —SOR⁴, —SO₂R⁴, —SO₂NR¹R², —COR¹, —CO₂R¹, —CONR¹R²,—C(═NR¹)R², or —C(═NOR¹)R² substituents, wherein optionally twosubstituents are combined to form a cycloalkyl or heterocycloalkyl ringfused to X; wherein the —C₁₋₆alkyl substituent, cycloalkyl ring, orheterocycloalkyl ring each optionally is further substituted with 1-5independent halogen, —CN, —C₁₋₆alkyl, —O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl),—O(aryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl), —N(C₀₋₆alkyl)(C₃₋₇cycloalkyl), or—N(C₀₋₆alkyl)(aryl) groups;

R¹, R², and R³ each independently is —C₀₋₆alkyl, —C₃₋₇cycloalkyl,heteroaryl, or aryl; any of which is optionally substituted with 1-5independent halogen, —CN, —C₁₋₆alkyl, —O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl),—O(aryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl), —N(C₀₋₆alkyl)(C₃₋₇cycloalkyl),—N(C₀₋₆alkyl)(aryl) substituents;

R⁴ is —C₁₋₆alkyl, —C₃₋₇cycloalkyl, heteroaryl, or aryl; optionallysubstituted with 1-5 independent halogen, —CN, —C₁₋₆alkyl,—O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl), —O(aryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl),—N(C₀₋₆alkyl)(C₃₋₇cycloalkyl), —N(C₀₋₆alkyl)(aryl) substituents;

A is —(C₀₋₄alkyl, —C₀₋₂alkyl-SO—C₀₋₂alkyl-, —C₀₋₂alkyl-SO₂—C₀₋₂alkyl-,—C₀₋₂alkyl-CO—C₀₋₂alkyl-, —(C₀₋₂alkyl-NR⁹CO—(C₀₋₂alkyl-,—(C₀₋₂alkyl-NR⁹SO₂—C₀₋₂alkyl- or -heteroC₀₋₄alkyl;

W is —C₃₋₇cycloalkyl, -heteroC₃₋₇cycloalkyl, —C₀₋₆alkylaryl, or—C₀₋₆alkylheteroaryl optionally substituted with 1-7 independenthalogen, —CN, NO₂, —C₁₋₆alkyl, —C₁₋₆alkenyl, —C₁₋₆alkynyl, —OR¹, —NR¹R²,—C(═NR¹)NR²R³, —N(═NR¹)NR²R³, —NR¹COR², —NR¹CO₂R², —NR¹SO₂R⁴,—NR¹CONR²R³, —SR⁴, —SOR⁴, —SO₂R⁴, —SO₂NR¹R², —COR¹, —CO₂R¹, —CONR¹R²,—C(═NR¹)R², or —C(═NOR¹)R² substituents;

Y is 2-pyridyl optionally substituted with 1-4 independent halogen, —CN,NO₂, —C₁₋₆alkyl, —C₁₋₆alkenyl, —C₁₋₆alkynyl, —OR⁵, —NR⁵R⁶,—C(═NR⁵)NR⁶R⁷, —N(═NR⁵)NR⁶R⁷, —N(═NR⁵)NR⁶R⁷, —NR⁵COR⁶, —NR⁵CO₂R⁶,—NR⁵SO₂R⁸, —NR⁵CONR⁶R⁷, —SR⁸, —SOR⁸, —SO₂R⁸, —SO₂NR⁵R⁶, —COR⁵, —CO₂R⁵,—CONR⁵R⁶, —C(═NR⁵)R⁶, or —C(═NOR⁵)R⁶ substituents, wherein twosubstituents are combined to form a cycloalkyl or heterocycloalkyl ringfused to Y; wherein the —C₁₋₆alkyl substituent, cycloalkyl ring, orheterocycloalkyl ring each optionally is further substituted with 1-5independent halogen, —CN, —C₁₋₆alkyl, —O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl),—O(aryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl), —N(C₀₋₆alkyl)(C₃₋₇cycloalkyl), or—N(C₀₋₆alkyl)(aryl) groups;

R⁵, R⁶, and R⁷ each independently is —C₀₋₆alkyl, —C₃₋₇cycloalkyl,heteroaryl, or aryl; any of which is optionally substituted with 1-5independent halogen, —CN, —C₁₋₆alkyl, —O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl),—O(aryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl), —N(C₀₋₆alkyl)(C₃₋₇cycloalkyl),—N(C₀₋₆alkyl)(aryl) substituents;

R⁸ is —C₁₋₆alkyl, —C₃₋₇cycloalkyl, heteroaryl, or aryl; optionallysubstituted with 1-5 independent halogen, —CN, —C₁₋₆alkyl,—O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl), —O(aryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl),—N(C₀₋₆alkyl)(C₃₋₇cycloalkyl), —N(C₀₋₆alkyl)(aryl) substituents;

B is —C₀₋₄alkyl, —C₀₋₂alkyl-SO—C₀₋₂alkyl-, —C₀₋₂alkyl-SO₂—C₀₋₂alkyl-,—C₀₋₂alkyl-CO—C₀₋₂alkyl-, —C₀₋₂alkyl-NR¹⁰CO—C₀₋₂alkyl-,—C₀₋₂alkyl-NR¹⁰SO₂—C₀₋₂alkyl- or -heteroC₀₋₄alkyl;

R⁹ and R¹⁰ each independently is —C₀₋₆alkyl, —C₃₋₇cycloalkyl,heteroaryl, or aryl; any of which is optionally substituted with 1-5independent halogen, —CN, —C₁₋₆alkyl, —O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl),—O(aryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl), —N(C₀₋₆alkyl)(C₃₋₇cycloalkyl),—N(C₀₋₆alkyl)(aryl) substituents;

Z is —C₃₋₇cycloalkyl, -heteroC₃₋₇cycloalkyl, —C₀₋₆alkylaryl, or—C₀₋₆alkylheteroaryl optionally substituted with 1-7 independenthalogen, —CN, NO₂, —C₁₋₆alkyl, —C₁₋₆alkenyl, —C₁₋₆alkynyl, —OR¹, —NR¹R²,—C(═NR¹)NR²R³, —N(═NR¹)NR²R³, —NR¹COR², —NR¹CO₂R², —NR¹SO₂R⁴,—NR¹CONR²R³, —SR⁴, —SOR⁴, —SO₂R⁴, —SO₂NR¹R², —COR¹, —CO₂R¹, —CONR¹R²,—C(═NR¹)R², or —C(═NOR¹)R² substituents;

one of W and Z is optionally absent;

R¹¹ and R¹² is each independently halogen, —C₀₋₆alkyl, —C₀₋₆alkoxyl, ═O,═N(C₀₋₄alkyl),or —N(C₀₋₄alkyl)(C₀₋₄alkyl); and

any alkyl optionally substituted with 1-5 independent halogensubstituents, and any N may be an N-oxide.

In an embodiment of this second aspect, the compounds of this inventionare represented by Formula (I) or a pharmaceutically acceptable saltthereof, wherein:

X is phenyl optionally substituted with 1-5 independent halogen, —CN,NO₂, —C₁₋₆alkyl, —C₁₋₆alkenyl, —C₁₋₆alkynyl, —OR¹, —NR¹R²,—C(═NR¹)NR²R³, —N(═NR¹)NR¹R³, NR¹COR², —NR¹CO₂R², —NR¹SO₂R⁴,—NR¹CONR²R³, —SR⁴, —SOR⁴, —SO₂l R⁴, —SO₂NR¹R², —COR¹, —CO₂R¹, —CONR¹R²,—C(═NR¹)R², or —C(═NOR¹)R² substituents, wherein optionally twosubstituents are combined to form a cycloalkyl or heterocycloalkyl ringfused to X; wherein the —C₁₋₆alkyl substituent, cycloalkyl ring, orheterocycloalkyl ring each optionally is further substituted with 1-5independent halogen, —CN, —C₁₋₆alkyl, —O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl),—O(aryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl), —N(C₀₋₆alkyl)(C₃₋₇cycloalkyl), or—N(C₀₋₆alkyl)(aryl) groups;

R¹, R², and R³ each independently is —C₀₋₆alkyl, —C₃₋₇cycloalkyl,heteroaryl, or aryl; any of which is optionally substituted with 1-5independent halogen, —CN, —C₁₋₆alkyl, —O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl),—O(aryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl), —N(C₀₋₆alkyl)(C₃₋₇cycloalkyl),—N(C₀₋₆alkyl)(aryl) substituents;

R⁴ is —C₁₋₆alkyl, —C₃₋₇cycloalkyl, heteroaryl, or aryl; optionallysubstituted with 1-5 independent halogen, —CN, —C₁₋₆alkyl,—O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl), —O(aryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl),—N(C₀₋₆alkyl)(C₃₋₇cycloalkyl), —N(C₀₋₆alkyl)(aryl) substituents;

A is —C₀₋₄alkyl, —C₀₋₂alkyl-SO—C₀₋₂alkyl-, —C₀₋₂alkyl-SO₂—C₀₋₂alkyl-,—C₀₋₂alkyl-CO—C₀₋₂alkyl-, —C₀₋₂alkyl-NR⁹CO—C₀₋₂alkyl-,—C₀₋₂alkyl-NR⁹SO₂—C₀₋₂alkyl- or -heteroC₀₋₄alkyl;

W is —C₃₋₇cycloalkyl, -heteroC₃₋₇cycloalkyl, —C₀₋₆alkylaryl, or—C₀₋₆alkylheteroaryl optionally substituted with 1-7 independenthalogen, —CN, NO₂, —C₁₋₆alkyl, —C₁₋₆alkenyl, —C₁₋₆alkynyl, —OR¹, —NR¹R²,—C(═NR¹)NR²R³, —N(═NR¹)NR²R³, —NR¹COR², —NR¹CO₂R², —NR¹SO₂R⁴,—NR¹CONR²R³, —SR⁴, —SOR⁴, —SO₂R⁴, —SO₂NR¹R², —COR¹, —CO₂R¹, —CONR¹R²,—C(═NR¹)R², or —C(═NOR¹)R² substituents;

Y is 2-pyridyl optionally substituted with 1-4 independent halogen, —CN,NO₂, —C₁₋₆alkyl, —C₁₋₆alkenyl, —C₁₋₆alkynyl, —OR⁵, —NR⁵R⁶,—C(═NR⁵)NR⁶R⁷, —N(═NR⁵)NR⁶R⁷, —NR⁵COR⁶, —NR⁵CO₂R⁶, —NR⁵SO₂R⁸,—NR⁵CONR⁶R⁷, —SR⁸, —SOR⁸, —SO₂R⁸, —SO₂NR⁵R⁶, —COR⁵, —CO₂R⁵, —CONR⁵R⁶,—C(═NR⁵)R⁶, or —C(═NOR⁵)R⁶ substituents, wherein optionally twosubstituents are combined to form a cycloalkyl or heterocycloalkyl ringfused to Y; wherein the —C₁₋₆alkyl substituent, cycloalkyl ring, orheterocycloalkyl ring each optionally is further substituted with 1-5independent halogen, —CN, —C₁₋₆alkyl, —O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl),—O(aryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl), —N(C₀₋₆alkyl)(C₃₋₇cycloalkyl), or—N(C₀₋₆alkyl)(aryl) groups;

R⁵, R⁶, and R⁷ each independently is —C₀₋₆alkyl, —C₃₋₇cycloalkyl,heteroaryl, or aryl; any of which is optionally substituted with 1-5independent halogen, —CN, —C₁₋₆alkyl, —O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl),—O(aryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl), —N(C₀₋₆alkyl)(C₃₋₇cycloalkyl),—N(C₀₋₆alkyl)(aryl) substituents;

R⁸ is —C₁₋₆alkyl, —C₃₋₇cycloalkyl, heteroaryl, or aryl; optionallysubstituted with 1-5 independent halogen, —CN, —C₁₋₆alkyl,—O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl), —O(aryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl),—N(C₀₋₆alkyl)(C₃₋₇cycloalkyl), —N(C₀₋₆alkyl)(aryl) substituents;

B is —C₀₋₄alkyl, —C₀₋₂alkyl-SO—CO₂alkyl-, —C₀₋₂alkyl-SO₂—C₀₋₂alkyl-,—C₀₋₂alkyl-CO—C₀₋₂alkyl-, —C₀₋₂alkyl-NR¹⁰CO—C₀₋₂alkyl-,—C₀₋₂alkyl-NR¹⁰SO₂—C₀₋₂alkyl- or -heteroC₀₋₄alkyl;

R⁹ and R¹⁰ each independently is —C₀₋₆alkyl, —C₃₋₇cycloalkyl,heteroaryl, or aryl; any of which is optionally substituted with 1-5independent halogen, —CN, —C₁₋₆alkyl, —O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl),—O(aryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl), —N(C₀₋₆alkyl)(C₃₋₇cycloalkyl),—N(C₀₋₆alkyl)(aryl) substituents;

Z is —C₃₋₇cycloalkyl, -heteroC₃₋₇cycloalkyl, —C₀₋₆alkylaryl, or—C₀₋₆alkylheteroaryl optionally substituted with 1-7 independenthalogen, —CN, NO₂, —C₁₋₆alkyl, —C₁₋₆alkenyl, —C₁₋₆alkynyl, —OR¹, —NR¹R²,—C(═NR¹)NR²R³, —N(═NR¹)NR²R³, —NR¹COR², —NR¹CO₂R², —NR¹SO₂R⁴,—NR¹CONR²R³, —SR⁴, —SOR⁴, —SO₂R⁴, —SO₂NR¹R², —COR¹, —CO₂R¹, —CONR¹R²,—C(═NR¹)R², or —C(═NOR¹)R² substituents;

one of W and Z is optionally absent;

R¹¹ and R¹² is each independently halogen, —C₀₋₆alkyl, —C₀₋₆alkoxyl, ═O,═N(C₀₋₄alkyl),or —N(C₀₋₄alkyl)(C₀₋₄alkyl); and

any alkyl optionally substituted with 1-5 independent halogensubstituents, and any N may be an N-oxide.

In a third aspect, the compounds of this invention are represented byFormula (I) or a pharmaceutically acceptable salt thereof, wherein:

X is phenyl optionally substituted with 1-5 independent halogen, —CN,NO₂, —C₁₋₆alkyl, —C₁₋₆alkenyl, —C₁₋₆alkynyl, —OR¹, —NR¹R²,—C(═NR¹)NR²R³, —N(═NR¹)NR²R³, —NR¹COR², —NR¹CO₂R², —NR¹SO₂R⁴,—NR¹CONR²R³, —SR⁴, —SOR⁴, —SO₂R⁴, —SO₂NR¹R², —COR¹, —CO₂R¹, —CONR¹R²,—C(═NR¹)R², or —C(═NOR¹)R² substituents, wherein optionally twosubstituents are combined to form a cycloalkyl or heterocycloalkyl ringfused to X; wherein the —C₁₋₆alkyl substituent, cycloalkyl ring, orheterocycloalkyl ring each optionally is further substituted with 1-5independent halogen, —CN, —C₁₋₆alkyl, —O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl),—O(aryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl), —N(C₀₋₆alkyl)(C₃₋₇cycloalkyl), or—N(C₀₋₆alkyl)(aryl) groups;

R¹, R², and R³ each independently is —C₁₋₆alkyl, —C₃₋₇cycloalkyl,heteroaryl, or aryl; any of which is optionally substituted with 1-5independent halogen, —CN, —C₁₋₆alkyl, —O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl),—O(aryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl), —N(C₀₋₆alkyl)(C₃₋₇cycloalkyl),—N(C₀₋₆alkyl)(aryl) substituents;

R⁴ is —C₁₋₆alkyl, —C₃₋₇cycloalkyl, heteroaryl, or aryl; optionallysubstituted with 1-5 independent halogen, —CN, —C₁₋₆alkyl,—O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl), —O(aryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl),—N(C₀₋₆alkyl)(C₃₋₇cycloalkyl), —N(C₀₋₆alkyl)(aryl) substituents;

A is —(C₀₋₄alkyl, —C₀₋₂alkyl-SO—C₀₋₂alkyl-, —C₀₋₂alkyl-SO₂—C₀₋₂alkyl-,—C₀₋₂alkyl-CO—C₀₋₂alkyl-, —C₀₋₂alkyl-NR⁹CO—C₀₋₂alkyl-,—(C₀₋₂alkyl-NR⁹SO₂—C₀₋₂alkyl- or -heteroC₀₋₄alkyl;

W is —C₃₋₇cycloalkyl, -heteroC₃₋₇cycloalkyl, —C₀₋₆alkylaryl, or—C₀₋₆alkylheteroaryl optionally substituted with 1-7 independenthalogen, —CN, NO₂, —C₁₋₆alkyl, —C₁₋₆alkenyl, —C₁₋₆alkynyl, —OR¹, —NR¹R²,—C(═NR¹)NR²R³, —N(═NR¹)NR²R³, —NR¹COR², —NR¹CO₂R², —NR¹SO₂R⁴,—NR¹CONR²R³, —SR⁴, —SOR⁴, —SO₂R⁴, —SO₂NR¹R², —COR¹, —CO₂R¹, —CONR¹R²,—C(═NR¹)R², or —C(═NOR¹)R² substituents;

Y is aryl or heteroaryl optionally substituted with 1-7 independenthalogen, —CN, NO₂, —C₁₋₆alkyl, —C₁₋₆alkenyl, —C₁₋₆alkynyl, —OR⁵, —NR⁵R⁶,—C(═NR⁵)NR⁶R⁷, —N(═NR⁵)NR⁶R⁷, —NR⁵COR⁶, —NR⁵CO₂R⁶, —NR⁵SO₂R⁸,—NR⁵CONR⁶R⁷, —SR⁸, —SOR⁸, —SO₂R⁸, —SO₂NR⁵R⁶, —COR⁵, —CO₂R⁵, —CONR⁵R⁶,—C(═NR⁵)R⁶ substituents, wherein optionally two substituents arecombined to form a cycloalkyl or heterocycloalkyl ring fused to Y;wherein the —C₁₋₆alkyl substituent, cycloalkyl ring, or heterocycloalkylring each optionally is further substituted with 1-5 independenthalogen, —CN, —C₁₋₆alkyl, —O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl), —O(aryl),—N(C₀₋₆alkyl)(C₀₋₆alkyl), —N(C₀₋₆alkyl)(C₃₋₇cycloalkyl), or—N(C₀₋₆alkyl)(aryl) groups;

R⁵, R⁶, and R⁷ each independently is —C₀₋₆alkyl, —C₃₋₇cycloalkyl,heteroaryl, or aryl; any of which is optionally substituted with 1-5independent halogen, —CN, —C₁₋₆alkyl, —O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl),—O(aryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl), —N(C₀₋₆alkyl)(C₃₋₇cycloalkyl),—N(C₀₋₆alkyl)(aryl) substituents;

R⁸ is —C₁₋₆alkyl, —C₃₋₇cycloalkyl, heteroaryl, or aryl; optionallysubstituted with 1-5 independent halogen, —CN, —C₁₋₆alkyl,—O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl), —O(aryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl),—N(C₀₋₆alkyl)(C₃₋₇cycloalkyl), —N(C₀₋₆alkyl)(aryl) substituents;

B is —(C₀₋₄alkyl, —C₀₋₂alkyl-SO—C₀₋₂alkyl-, —C₀₋₂alkyl-SO₂—C₀₋₂alkyl-,—C₀₋₂alkyl-CO—C₀₋₂alkyl-, —C₀₋₂alkyl-NR¹⁰CO—C₀₋₂alkyl-,—C₀₋₂alkyl-NR¹⁰SO₂—C₀₋₂alkyl- or -heteroC₀₋₄alkyl;

R⁹ and R¹⁰ each independently is —C₀₋₆alkyl, —C₃₋₇cycloalkyl,heteroaryl, or aryl; any of which is optionally substituted with 1-5independent halogen, —CN, —C₁₋₆alkyl, —O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl),—O(aryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl), —N(C₀₋₆alkyl)(C₃₋₇cycloalkyl),—N(C₀₋₆alkyl)(aryl) substituents;

Z is —C₃₋₇cycloalkyl, -heteroC₃₋₇cycloalkyl, —C₀₋₆alkylaryl, or—C₀₋₆alkylheteroaryl optionally substituted with 1-7 independenthalogen, —CN, NO₂, —C₁₋₆alkyl, —C₁₋₆alkenyl, —C₁₋₆alkynyl, —OR¹, —NR¹R²,—C(═NR¹)NR²R³, —N(═NR¹)NR²R³, —NR¹COR², —NR¹CO₂R², —NR¹SO₂R⁴,—NR¹CONR²R³, —SR⁴, —SOR⁴, —SO₂NR¹R², —COR¹, —CO₂R¹, —CONR¹R²,—C(═NR¹)R², or —C(═NOR¹)R² substituents;

one of W and Z is optionally absent;

R¹¹ and R¹² is each independently halogen, —C₀₋₆alkyl, —C₀₋₆alkoxyl, ═O,═N(C₀₋₄alkyl), or —N(C₀₋₄alkyl)(C₀₋₄alkyl); and

any alkyl optionally substituted with 1-5 independent halogensubstituents, and any N may be an N-oxide.

In a fourth aspect, the compounds of this invention are represented byFormula (I) or a pharmaceutically acceptable salt thereof, wherein:

X is aryl or heteroaryl optionally substituted with 1-7 independenthalogen, —CN, NO₂, —C₁₋₆alkyl, —C₁₋₆alkenyl, —C₁₋₆alkynyl, —OR¹, —NR¹R²,—C(═NR¹)NR²R³, —N(═NR¹)NR²R³, —NR¹COR², —NR¹CO₂R², —NR¹SO₂R⁴,—NR¹CONR²R³, —SR⁴, —SOR⁴, —SO₂R⁴, —SO₂NR¹R², —COR¹, —CO₂R¹, —CONR¹R²,—C(═NR¹)R², or —C(═NOR¹)R² substituents, wherein optionally twosubstituents are combined to form a cycloalkyl or heterocycloalkyl ringfused to X; wherein the —C₁₋₆alkyl substituent, cycloalkyl ring, orheterocycloalkyl ring each optionally is further substituted with 1-5independent halogen, —CN, —C₁₋₆alkyl, —O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl),—O(aryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl), —N(C₀₋₆alkyl)(C₃₋₇cycloalkyl), or—N(C₀₋₆alkyl)(aryl) groups;

R¹, R², and R³ each independently is —C₀₋₆alkyl, —C₃₋₇cycloalkyl,heteroaryl, or aryl; any of which is optionally substituted with 1-5independent halogen, —CN, —C₁₋₆alkyl, —O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl),—O(aryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl), —N(C₀₋₆alkyl)(C₃₋₇cycloalkyl),—N(C₀₋₆alkyl)(aryl) substituents;

R⁴ is —C₁₋₆alkyl, —C₃₋₇cycloalkyl, heteroaryl, or aryl; optionallysubstituted with 1-5 independent halogen, —CN, —C₁₋₆alkyl,—O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl), —O(aryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl),—N(C₀₋₆alkyl)(C₃₋₇cycloalkyl), —N(C₀₋₆alkyl)(aryl) substituents;

A is —C₀₋₄alkyl, —C₀₋₂alkyl-SO—C₀₋₂alkyl-, —C₀₋₂alkyl-SO₂—C₀₋₂alkyl-,—C₀₋₂alkyl-CO—C₀₋₂alkyl-, —C₀₋₂alkyl-NR⁹CO—C₂alkyl-,—C₂alkyl-NR⁹SO₂—C₂alkyl- or -heteroC₀₋₄alkyl;

W is —C₃₋₇cycloalkyl, -heteroC₃₋₇cycloalkyl, —C₀₋₆alkylaryl, or—C₀₋₆alkylheteroaryl optionally substituted with 1-7 independenthalogen, —CN, NO₂, —C₁₋₆alkyl, —C₁₋₆alkenyl, —C₁₋₆alkynyl, —OR¹, —NR¹R²,—C(═NR¹)NR²R³, —N(═NR¹)NR²R³, —N(═NR¹)NR²R³, —NR¹COR², —NR¹CO₂R²,—NR¹SO₂R⁴, —NR¹CONR²R³, —SR⁴, —SOR⁴, —SO₂R⁴, —SO₂NR¹R², —COR¹, —CO₂R¹,—CONR¹R², —C(═NR¹)R², or —C(═NOR¹)R² substituents;

Y is phenyl optionally substituted with 1-5 independent halogen, —CN,NO₂, —C₁₋₆alkyl, —C₁₋₆alkenyl, —C₁₋₆alkynyl, —OR⁵, —NR⁵R⁶,—C(═NR⁵)NR⁶R⁷, —N(═NR₆R⁷, —NR⁵COR⁶, —NR⁵CO₂R⁶, —NR⁵SO₂R⁸, —NR⁵CONR⁶R⁷,—SR⁸, —SOR⁸, —SO₂R⁸, —SO₂NR⁵R⁶, —COR⁵, —CO₂R⁵, —CONR⁵R⁶, —C(═NR⁵)R⁶, or—C(═NOR⁵)R⁶ substituents, wherein optionally two substituents arecombined to form a cycloalkyl or heterocycloalkyl ring fused to Y;wherein the —C₁₋₆alkyl substituent, cycloalkyl ring, or heterocycloalkylring each optionally is further substituted with 1-5 independenthalogen, —CN, —C₁₋₆alkyl, —O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl), —O(aryl),—N(C₀₋₆alkyl)(C₀₋₆alkyl), —N(C₀₋₆alkyl)(C₃₋₇cycloalkyl), or—N(C₀₋₆alkyl)(aryl) groups;

R⁵, R⁶, and R⁷ each independently is —C₀₋₆alkyl, —C₃₋₇cycloalkyl,heteroaryl, or aryl; any of which is optionally substituted with 1-5independent halogen, —CN, —C₁₋₆alkyl, —O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl),—O(aryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl), —N(C₀₋₆alkyl)(C₃₋₇cycloalkyl),—N(C₀₋₆alkyl)(aryl) substituents;

R⁸ is —C₁₋₆alkyl, —C₃₋₇cycloalkyl, heteroaryl, or aryl; optionallysubstituted with 1-5 independent halogen, —CN, —C₁₋₆alkyl,—O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl), —O(aryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl),—N(C₀₋₆alkyl)(C₃₋₇cycloalkyl), —N(C₀₋₆alkyl)(aryl) substituents;

B is —(C₀₋₄alkyl, —C₀₋₂alkyl-SO—C₀₋₂alkyl-, —C₀₋₂alkyl-SO₂—C₀₋₂alkyl-,—C₀₋₂alkyl-CO—C₀₋₂alkyl-, —C₀₋₂alkyl-NR¹⁰CO—C₀₋₂alkyl-,—C₀₋₂alkyl-NR¹⁰SO₂—C₀₋₂alkyl- or-heteroC₀₋₄alkyl;

R⁹ and R¹⁰ each independently is —C₀₋₆alkyl, —C₃₋₇cycloalkyl,heteroaryl, or aryl; any of which is optionally substituted with 1-5independent halogen, —CN, —C₁₋₆alkyl, —O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl),—O(aryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl), —N(C₀₋₆alkyl)(C₃₋₇cycloalkyl),—N(C₀₋₆alkyl)(aryl) substituents;

Z is C₃₋₇cycloalkyl, -heteroC₃₋₇cycloalkyl, —C₀₋₆alkylaryl, or—C₀₋₆alkylheteroaryl optionally substituted with 1-7 independenthalogen, —CN, NO₂, —C₁₋₆alkyl, —C₁₋₆alkenyl, —C₁₋₆alkynyl, —OR¹, —NR¹R²,—C(═NR¹)NR²R³, —N(═NR¹)NR²R³, —NR¹COR², —NR¹CO₂R², —NR¹SO₂R⁴,—NR¹CONR²R³, —SR⁴, —SOR⁴, —SO₂ ₂R⁴, —SO₂NR¹R², —COR¹, —CO₂R¹, —CONR¹R²,—C(═NR¹)R², or —C(═NOR¹)R² substituents;

one of W and Z is optionally absent;

R¹¹ and R¹² is each independently halogen, —C₀₋₆alkyl, —C₀₋₆alkoxyl, ═O,═N(C₀₋₄alkyl),or —N(C₀₋₄alkyl)(C₀₋₄alkyl); and

any alkyl optionally substituted with 1-5 independent halogensubstituents, and any N may be an N-oxide.

In a fifth aspect, the compounds of this invention are represented byFormula (I) or a pharmaceutically acceptable salt thereof, wherein:

X is aryl or heteroaryl optionally substituted with 1-7 independenthalogen, —CN, NO₂, —C₁₋₆alkyl, —C₁₋₆alkenyl, —C₁₋₆alkynyl, —OR¹, —NR¹R²,—C(═NR¹)NR²R³, —N(═NR¹)NR²R³, —NR¹COR², —NR¹CO₂R², —NR¹SO₂R⁴,—NR¹CONR²R³, —SR⁴, —SOR⁴, —SO₂R⁴, —SO₂NR¹R², —COR¹, —CO₂R¹, —CONR¹R²,—C(═NR¹)R², or —C(═NOR¹)R² substituents, wherein optionally twosubstituents are combined to form a cycloalkyl or heterocycloalkyl ringfused to X; wherein the —C₁₋₆alkyl substituent, cycloalkyl ring, orheterocycloalkyl ring each optionally is further substituted with 1-5independent halogen, —CN, —C₁₋₆alkyl, —O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl),—O(aryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl), —N(C₀₋₆alkyl)(C₃₋₇cycloalkyl), or—N(C₀₋₆alkyl)(aryl) groups;

R¹, R², and R³ each independently is —C₀₋₆alkyl, —C₃₋₇cycloalkyl,heteroaryl, or aryl; any of which is optionally substituted with 1-5independent halogen, —CN, —C₁₋₆alkyl, —O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl),—O(aryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl), —N(C₀₋₆alkyl)(C₃₋₇cycloalkyl),—N(C₀₋₆alkyl)(aryl) substituents;

R⁴ is —C₁₋₆alkyl, —C₃₋₇cycloalkyl, heteroaryl, or aryl; optionallysubstituted with 1-5 independent halogen, —CN, —C₁₋₆alkyl,—O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl), —O(aryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl),—N(C₀₋₆alkyl)(C₃₋₇cycloalkyl), —N(C₀₋₆alkyl)(aryl) substituents;

A is —C₀₋₄alkyl, —C₀₋₂alkyl-SO—C₀₋₂alkyl-, —C₀₋₂alkyl-SO₂—C₀₋₂alkyl-,—C₀₋₂alkyl-CO—C₀₋₂alkyl-, —C₀₋₂alkyl-NR⁹CO—C₀₋₂alkyl-,—C₀₋₂alkyl-NR⁹SO₂—C₀₋₂alkyl- or —heteroC₀₋₄alkyl;

W is —C₃₋₇cycloalkyl, -heteroC₃₋₇cycloalkyl, —C₀₋₆alkylaryl, or—C₀₋₆alkylheteroaryl optionally substituted with 1-7 independenthalogen, —CN, NO₂, —C₁₋₆alkyl, —C₁₋₆alkenyl, —C₁₋₆alkynyl, —OR¹, —NR¹R²,—C(═NR¹)NR²R³, —N(═NR¹)NR²R³, —NR¹COR², —NR¹CO₂R², —NR¹SO₂R⁴,—NR¹CONR²R³, —SR⁴, —SOR⁴, —SO₂R⁴, —SO₂NR¹R², —COR¹, —CO₂R¹, —CONR¹R²,—C(═NR¹)R², or —C(═NOR¹)R² substituents;

Y is aryl or heteroaryl optionally substituted with 1-7 independenthalogen, —CN, NO₂, —C₁₋₆alkyl, —C₁₋₆alkenyl, —C₁₋₆alkynyl, —OR⁵, —NR⁵R⁶,—C(═NR⁵)NR⁶R⁷, —N(═NR⁵)NR⁶R⁷, —NR⁵COR⁶, —NR⁵CO₂R⁶, —NR⁵SO₂R⁸,—NR⁵CONR⁶R⁷, —SR⁸, —SOR⁸, —SO₂R⁸, —SO₂NR⁵R⁶, —COR⁵, —CO₂R⁵, —CONR⁵R⁶,—C(═NR⁵)R⁶, —C(═NOR⁵)R⁶ substituents, wherein optionally twosubstituents are combined to form a cycloalkyl or heterocycloalkyl ringfused to Y; wherein the —C₁₋₆alkyl substituent, cycloalkyl ring, orheterocycloalkyl ring each optionally is further substituted with 1-5independent halogen, —CN, —C₁₋₆alkyl, —O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl),—O(aryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl), —N(C₀₋₆alkyl)(C₃₋₇cycloalkyl), or—N(C₀₋₆alkyl)(aryl) groups;

R⁵, R⁶, and R⁷ each independently is —C₀₋₆alkyl, —C₃₋₇cycloalkyl,heteroaryl, or aryl; any of which is optionally substituted with 1-5independent halogen, —CN, —C₁₋₆alkyl, —O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl),—O(aryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl), —N(C₀₋₆alkyl)(C₃₋₇cycloalkyl),—N(C₀₋₆alkyl)(aryl) substituents;

R⁸ is —C₁₋₆alkyl, —C₃₋₇cycloalkyl, heteroaryl, or aryl; optionallysubstituted with 1-5 independent halogen, —CN, —C₁₋₆alkyl,—O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl), —O(aryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl),—N(C₀₋₆alkyl)(C₃₋₇cycloalkyl), —N(C₀₋₆alkyl)(aryl) substituents;

B is —C₀₋₄alkyl, —C₀₋₂alkyl-SO—C₀₋₂alkyl-, —C₀₋₂alkyl-SO₂—C₀₋₂alkyl-,—C₀₋₂alkyl-CO —C₀₋₂alkyl-, —C₀₋₂alkyl-NR¹⁰CO—C₀₋₂alkyl-,—C₀₋₂alkyl-NR¹⁰SO₂—C₀₋₂alkyl- or -heteroC₀₋₄alkyl;

R⁹ and R¹⁰ each independently is —C₀₋₆alkyl, —C₃₋₇cycloalkyl,heteroaryl, or aryl; any of which is optionally substituted with 1-5independent halogen, —CN, —C₁₋₆alkyl, —O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl),—O(aryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl), —N(C₀₋₆alkyl)(C₃₋₇cycloalkyl),—N(C₀₋₆alkyl)(aryl) substituents;

Z is —C₀₋₆alkylaryl or —C₀₋₆alkylheteroaryl optionally substituted with1-7 independent halogen, —CN, NO₂, —C₁₋₆alkyl, —C₁₋₆alkenyl,—C₁₋₆alkynyl, —OR¹, —NR¹R², —C(═NR¹)NR²R³, —N(═NR¹)NR²R³, —NR¹COR²,—NR¹CO₂R², —NR¹SO₂R⁴, —NR¹CONR²R³, —SR⁴, —SOR⁴, —SO₂R⁴, —SO₂NR¹R²,—COR¹, —CO₂R¹, —CONR¹R², —C(═NR¹)R², or —C(═NOR¹)R² substituents;

one of W and Z is optionally absent;

R¹¹ and R¹² is each independently halogen, —C₀₋₆alkyl, —C₀₋₆alkoxyl, ═O,═N(C₀₋₄alkyl),or —N(C₀₋₄alkyl)(C₀₋₄alkyl); and

any alkyl optionally substituted with 1-5 independent halogensubstituents, and any N may be an N-oxide.

In a sixth aspect, the compounds of this invention are represented byFormula (I) or a pharmaceutically acceptable salt thereof, wherein:

X is aryl or heteroaryl optionally substituted with 1-7 independenthalogen, —CN, NO₂, —C₁₋₆alkyl, —C₁₋₆alkenyl, —C₁₋₆alkynyl, —OR¹, —NR¹R²,—C(═NR¹)NR²R³, —N(═NR¹)NR²R³, —NR¹COR², —NR¹CO₂R², —NR¹SO₂R⁴,—NR¹CONR²R³, —SR⁴, —SOR⁴, —SO₂R⁴, —SO₂NR¹R², —COR¹, —CO₂R¹, —CONR¹R²,—C(═NR¹)R², or —C(═NOR¹)R² substituents, wherein optionally twosubstituents are combined to form a cycloalkyl or heterocycloalkyl ringfused to X; wherein the —C₁₋₆alkyl substituent, cycloalkyl ring, orheterocycloalkyl ring each optionally is further substituted with 1-5independent halogen, —CN, —C₁₋₆alkyl, —O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl),—O(aryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl), —N(C₀₋₆alkyl)(C₃₋₇cycloalkyl), or—N(C₀₋₆alkyl)(aryl) groups;

R¹, R², and R³ each independently is —C₀₋₆alkyl, —C₃₋₇cycloalkyl,heteroaryl, or aryl; any of which is optionally substituted with 1-5independent halogen, —CN, —C₁₋₆alkyl, —O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl),—O(aryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl), —N(C₀₋₆alkyl)(C₃₋₇cycloalkyl),—N(C₀₋₆alkyl)(aryl) substituents;

R⁴ is —C₁₋₆alkyl, —C₃₋₇cycloalkyl, heteroaryl, or aryl; optionallysubstituted with 1-5 independent halogen, —CN, —C₁₋₆alkyl,—O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl), —O(aryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl),—N(C₀₋₆alkyl)(C₃₋₇cycloalkyl), —N(C₀₋₆alkyl)(aryl) substituents;

A is —C₀₋₄alkyl, —C₀₋₂alkyl-SO—C₀₋₂alkyl-, —C₀₋₂alkyl-SO₂—C₀₋₂alkyl-,—C₀₋₂alkyl-CO—C₀₋₂alkyl-, —C₀₋₂alkyl-NR⁹CO—C₀₋₂alkyl-,—C₀₋₂alkyl-NR⁹SO₂—C₀₋₂alkyl- or -heteroC₀₋₄alkyl;

W is —C₀₋₆alkylaryl or —C₀₋₆alkylheteroaryl optionally substituted with1-7 independent halogen, —CN, NO₂, —C₁₋₆alkyl, —C₁₋₆alkenyl,—C₁₋₆alkynyl, —OR¹, —NR¹R², —C(═NR¹)NR²R³, —N(═NR¹)NR²R³, —NR¹COR²,—NR¹CO₂R², —NR¹SO₂R⁴, —NR¹CONR²R³, —SR⁴, —SOR⁴, —SO₂R⁴, —SO₂NR¹R²,—COR¹, —CO₂R¹, —CONR¹R², —C(═NR¹)R², or —C(═NOR¹)R² substituents;

Y is aryl or heteroaryl optionally substituted with 1-7 independenthalogen, —CN, NO₂, —C₁₋₆alkyl, —C₁₋₆alkenyl, —C₁₋₆alkynyl, —OR⁵, —NR⁵R⁶,—C(═NR⁵)NR⁶R⁷, —N(═NR⁵)NR⁶R⁷, —NR⁵COR⁶, —NR⁵CO₂R⁶, —NR⁵SO₂R⁸,—NR⁵CONR⁶R⁷, —SR⁸, —SOR⁸, —SO₂R⁸, —SO₂NR⁵R⁶, —COR⁵, —CO₂R⁵, —CONR⁵R⁶,—C(═NR⁵)R⁶ substituents, wherein optionally two substituents arecombined to form a cycloalkyl or heterocycloalkyl ring fused to Y;wherein the —C₁₋₆alkyl substituent, cycloalkyl ring, or heterocycloalkylring each optionally is further substituted with 1-5 independenthalogen, —CN, —C₁₋₆alkyl, —O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl), —O(aryl),—N(C₀₋₆alkyl)(C₀₋₆alkyl), —N(C₀₋₆alkyl)(C₃₋₇cycloalkyl), or—N(C₀₋₆alkyl)(aryl) groups;

R⁵, R⁶, and R⁷ each independently is —C₀₋₆alkyl, —C₃₋₇cycloalkyl,heteroaryl, or aryl; any of which is optionally substituted with 1-5independent halogen, —CN, —C₁₋₆alkyl, —O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl),—O(aryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl), —N(C₀₋₆alkyl)(C₃₋₇cycloalkyl),—N(C₀₋₆alkyl)(aryl) substituents;

R⁸ is —C₁₋₆alkyl, —C₃₋₇cycloalkyl, heteroaryl, or aryl; optionallysubstituted with 1-5 independent halogen, —CN, —C₁₋₆alkyl,—O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl), —O(aryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl),—N(C₀₋₆alkyl)(C₃₋₇cycloalkyl), —N(C₀₋₆alkyl)(aryl) substituents;

B is —C₀₋₄alkyl, —C₀₋₂alkyl-SO—C₀₋₂alkyl-, —C₀₋₂alkyl-SO₂—C₀₋₂alkyl-,—C₀₋₂alkyl-CO—C₀₋₂alkyl-, —C₀₋₂alkyl-NR¹⁰CO—C₀₋₂alkyl-,—C₀₋₂alkyl-NR¹⁰SO₂—C₀₋₂alkyl- or -heteroC₀₋₄alkyl;

R⁹ and R¹⁰ each independently is —C₀₋₆alkyl, —C₃₋₇cycloalkyl,heteroaryl, or aryl; any of which is optionally substituted with 1-5independent halogen, —CN, —C₁₋₆alkyl, —O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl),—O(aryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl), —N(C₀₋₆alkyl)(C₃₋₇cycloalkyl),—N(C₀₋₆alkyl)(aryl) substituents;

Z is —C₃₋₇cycloalkyl, -heteroC₃₋₇cycloalkyl, —C₀₋₆alkylaryl, or—C₀₋₆alkylheteroaryl optionally substituted with 1-7 independenthalogen, —CN, NO₂, —C₁₋₆alkyl, —C₁₋₆alkenyl, —C₁₋₆alkynyl, —OR¹, —NR¹R²,—C(═NR¹)NR²R³, —N(═NR¹)NR²R³, —NR¹COR², —NR¹CO₂R², —NR¹SO₂R⁴,—NR¹CONR²R³, —SR⁴, —SOR⁴, —SO₂R⁴, —SO₂NR¹R², —COR¹, —CO₂R¹, —CONR¹R²,—C(═NR¹)R², or —C(═NOR¹)R² substituents;

one of W and Z is optionally absent;

R¹¹ and R¹² is each independently halogen, —C₀₋₆alkyl, —C₀₋₆alkoxyl, ═O,═N(C₀₋₄alkyl),or —N(C₀₋₄alkyl)(C₀₋₄alkyl); and

any alkyl optionally substituted with 1-5 independent halogensubstituents, and any N may be an N-oxide.

In a second embodiment of the first aspect, the compounds of thisinvention are represented by Formula (I) or a pharmaceuticallyacceptable salt thereof, wherein:

X is 2-pyridyl optionally substituted with 1-4 independent halogen, —CN,NO₂, —C₁₋₆alkyl, —C₁₋₆alkenyl, —C₁₋₆alkynyl, —OR¹, —NR¹R²,—C(═NR¹)NR²R³, —N(═NR¹)NR^(2R) ³, —NR ¹COR², —NR¹CO₂R², —NR¹SO₂R⁴,—NR¹CONR²R³, —SR⁴, —SOR⁴, —SO₂NR¹R², —COR¹, —CO₂R¹, —CONR¹R²,—C(═NR¹)R², or —C(═NOR¹)R² substituents, wherein optionally twosubstituents are combined to form a cycloalkyl or heterocycloalkyl ringfused to X; wherein the —C₁₋₆alkyl substituent, cycloalkyl ring, orheterocycloalkyl ring each optionally is further substituted with 1-5independent halogen, —CN, —C₁₋₆alkyl, —O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl),—O(aryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl), —N(C₀₋₆alkyl)(C₃₋₇cycloalkyl), or—N(C₀₋₆alkyl)(aryl) groups;

R¹, R², and R³ each independently is —C₀₋₆alkyl, —C₃₋₇cycloalkyl,heteroaryl, or aryl; any of which is optionally substituted with 1-5independent halogen, —CN, —C₁₋₆alkyl, —O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl),—O(aryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl), —N(C₀₋₆alkyl)(C₃₋₇cycloalkyl),—N(C₀₋₆alkyl)(aryl) substituents;

R⁴ is —C₁₋₆alkyl, —C₃₋₇cycloalkyl, heteroaryl, or aryl; optionallysubstituted with 1-5 independent halogen, —CN, —C₁₋₆alkyl,—O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl), —O(aryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl),—N(C₀₋₆alkyl)(C₃₋₇cycloalkyl), —N(C₀₋₆alkyl)(aryl) substituents;

A is —C₀₋₄alkyl, —C₀₋₂alkyl-SO—C₀₋₂alkyl-, —C₀₋₂alkyl-SO2—C₀₋₂alkyl-,—C₀₋₂alkyl-CO—C₀₋₂alkyl-, —C₀₋₂alkyl-NR⁹CO—C₀₋₂alkyl-,—C₀₋₂alkyl-NR⁹SO₂—C₀₋₂alkyl- or -heteroC₀₋₄alkyl;

W is —C₀₋₆cycloalkyl or —C₀₋₆heterocycloalkyl, —C₀₋₆alkylaryl or—C₀₋₆alkylheteroaryl optionally substituted with 1-7 independenthalogen, —CN, NO₂, —C₁₋₆alkyl, —C₁₋₆alkenyl, —C₁₋₆alkynyl, —OR¹, —NR¹R²,—C(═NR¹)NR²R³, —N(═NR¹)NR²R³, —NR¹COR², —NR¹CO₂R², —NR¹SO₂R⁴,—NR¹CONR²R³, —SR⁴, —SOR⁴, —SO₂R⁴, —SO₂NR¹R², —COR¹, —CO₂R¹, —CONR¹R²,—C(═NR¹)R², or —C(═NOR¹)R² substituents;

Y is phenyl optionally substituted with 1-5 independent halogen, —CN,NO₂, —C₁₋₆alkyl, —C₁₋₆alkenyl, —C₁₋₆alkynyl, —OR⁵, —NR⁵R⁶,—C(═NR⁵)NR⁶R⁷, —N(═NR⁵)NR⁶R⁷, —NR⁵COR⁶, —NR⁵CO₂R⁶, —NR⁵SO₂R⁸,—NR⁵CONR⁶R⁷, —SR⁸, —SOR⁸, —SO₂R⁸, —SO₂NR⁵R⁶, —COR⁵, —CO₂R⁵, —CONR⁵R⁶,—C(═NR⁵)R⁶, or —(═NOR⁵)R⁶ substituents, wherein optionally twosubstituents are combined to form a cycloalkyl or heterocycloalkyl ringfused to Y; wherein the —C₁₋₆alkyl substituent, cycloalkyl ring, orheterocycloalkyl ring each optionally is further substituted with 1-5independent halogen, —CN, —C₁₋₆alkyl, —O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl),—O(aryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl), —N(C₀₋₆alkyl)(C₃₋₇cycloalkyl), or—N(C₀₋₆alkyl)(aryl) groups;

R⁵, R⁶, and R⁷ each independently is —C₀₋₆alkyl, —C₃₋₇cycloalkyl,heteroaryl, or aryl; any of which is optionally substituted with 1-5independent halogen, —CN, —C₁₋₆alkyl, —O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl),—O(aryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl), —N(C₀₋₆alkyl)(C₃₋₇cycloalkyl),—N(C₀₋₆alkyl)(aryl) substituents;

R⁸ is —C₁₋₆alkyl, —C₃₋₇cycloalkyl, heteroaryl, or aryl; optionallysubstituted with 1-5 independent halogen, —CN, —C₁₋₆alkyl,—O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl), —O(aryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl),—N(C₀₋₆alkyl)(C₃₋₇cycloalkyl), —N(C₀₋₆alkyl)(aryl) substituents;

B is —(C₀₋₄alkyl, —C₀₋₂alkyl-SO—C₀₋₂alkyl-, —C₀₋₂alkyl-SO₂—C₀₋₂alkyl-,—C₀₋₂alkyl-CO—C₀₋₂alkyl-, —C₀₋₂alkyl-NR¹⁰CO—C₀₋₂alkyl-,—C₀₋₂alkyl-NR¹⁰SO₂—C₀₋₂alkyl- or -heteroC₀₋₄alkyl;

R⁹ and R¹⁰ each independently is —C₀₋₆alkyl, —C₃₋₇cycloalkyl,heteroaryl, or aryl; any of which is optionally substituted with 1-5independent halogen, —CN, —C₁₋₆alkyl, —O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl),—O(aryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl), —N(C₀₋₆alkyl)(C₃₋₇cycloalkyl),—N(C₀₋₆alkyl)(aryl) substituents;

Z is —C₀₋₆alkylaryl or —C₀₋₆alkylheteroaryl optionally substituted with1-7 independent halogen, —CN, NO₂, —C₁₋₆alkyl, —C₁₋₆alkenyl,—C₁₋₆alkynyl, —OR¹, —NR¹R², —C(═NR¹)NR²R³, —N(═NR¹)NR²R³, —NR¹COR²,—NR¹CO₂R², —NR¹SO₂R⁴, —NR¹CONR²R³, —SR⁴, —SOR⁴, —SO₂R⁴, —SO₂NR¹R²,—COR¹, —CO₂R¹, —CONR¹R², —C(═NR¹)R², or —C(═NOR¹)R² substituents;

one of W and Z is optionally absent;

R¹¹ and R¹² is each independently halogen, —C₀₋₆alkyl, —C₀₋₆alkoxyl, ═O,═N(C₀₋₄alkyl),or —N(C₀₋₄alkyl)(C₀₋₄alkyl); and

any alkyl optionally substituted with 1-5 independent halogensubstituents, and any N may be an N-oxide.

In a second embodiment of this second aspect, the compounds of thisinvention are represented by Formula (1) or a pharmaceuticallyacceptable salt thereof, wherein:

X is phenyl optionally substituted with 1-5 independent halogen, —CN,NO₂, —C₁₋₆alkyl, —C₁₋₆alkenyl, —C₁₋₆alkynyl, —OR¹, —NR¹R²,—C(═NR¹)NR²R³, —N(═NR¹)NR²R³, —NR¹COR², —NR¹CO₂R², —NR¹SO₂R⁴,—NR¹CONR²R³, —SR⁴, —SOR⁴, —SO₂R⁴, —SO₂NR¹R², —COR¹, —CO₂R¹, —CONR¹R²,—C(═NR¹)R², or —C(═NOR¹)R² substituents, wherein optionally twosubstituents are combined to form a cycloalkyl or heterocycloalkyl ringfused to X; wherein the —C₁₋₆alkyl substituent, cycloalkyl ring, orheterocycloalkyl ring each optionally is further substituted with 1-5independent halogen, —CN, —C₁₋₆alkyl, —O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl),—O(aryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl), —N(C₀₋₆alkyl)(C₃₋₇cycloalkyl), or—N(C₀₋₆alkyl)(aryl) groups;

R¹, R², and R³ each independently is —C₀₋₆alkyl, —C₃₋₇cycloalkyl,heteroaryl, or aryl; any of which is optionally substituted with 1-5independent halogen, —CN, —C₁₋₆alkyl, —O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl),—O(aryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl), —N(C₀₋₆alkyl)(C₃₋₇cycloalkyl),—N(C₀₋₆alkyl)(aryl) substituents;

R⁴ is —C₁₋₆alkyl, —C₃₋₇cycloalkyl, heteroaryl, or aryl; optionallysubstituted with 1-5 independent halogen, —CN, —C₁₋₆alkyl,—O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl), —O(aryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl),—N(C₀₋₆alkyl)(C₃₋₇cycloalkyl), —N(C₀₋₆alkyl)(aryl) substituents;

A is —C₀₋₄alkyl, —C₀₋₂alkyl-SO—C₀₋₂alkyl-, —C₀₋₂alkyl-SO₂—C₀₋₂alkyl-—C₀₋₂alkyl-CO—C₀₋₂alkyl-, —(C₀₋₂alkyl-NR⁹CO—C₀₋₂alkyl-,—C₀₋₂alkyl-NR⁹SO₂—C₀₋₂alkyl- or —heteroC₀₋₄alkyl;

W is —C₀₋₆alkylaryl or —C₀₋₆alkylheteroaryl optionally substituted with1-7 independent halogen, —CN, NO₂, —C₁₋₆alkyl, —C₁₋₆alkenyl,—C₁₋₆alkynyl, —OR¹, —NR¹R², —C(═NR¹)NR²R³, —N(═NR¹)NR²R³, —NR¹COR²,—NR¹CO₂R², —NR¹SO₂R⁴, —NR¹CONR²R³, —SR⁴, —SOR⁴, —SO₂R⁴, —SO₂NR¹R²,—COR¹, —CO₂R¹, —CONR¹R², —C(═NR ¹)R², or —C(═NOR¹)R² substituents;

Y is 2-pyridyl optionally substituted with 1-4 independent halogen, —CN,NO₂, —C₁₋₆alkyl, —C₁₆alkenyl, —C₁₋₆alkynyl, —OR⁵, —NR⁵R⁶, —C(═NR⁵)NR⁶R⁷,—N(═NR⁵)NR⁶R⁷, —NR⁵COR⁶, —NR⁵CO₂R⁶, —NR⁵SO₂R⁸, —NR⁵CONR⁶R⁷, —SR⁸, —SOR⁸,—SO₂R⁸, —SO₂NR⁵R⁶, —COR⁵, —CO₂R⁵, —CONR⁵R⁶, —C(═NR⁵)R⁶, or —C(═NOR⁵)R⁶substituents, wherein two substituents are combined to form a cycloalkylor heterocycloalkyl ring fused to Y; wherein the —C₁₋₆alkyl substituent,cycloalkyl ring, or heterocycloalkyl ring each optionally is furthersubstituted with 1-5 independent halogen, —CN, —C₁₋₆alkyl,—O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl), —O(aryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl),—N(C₀₋₆alkyl)(C₃₋₇cycloalkyl), or —N(C₀₋₆alkyl)(aryl) groups;

R⁵, R⁶, and R⁷ each independently is —C₀₋₆alkyl, —C₃₋₇cycloalkyl,heteroaryl, or aryl; any of which is optionally substituted with 1-5independent halogen, —CN, —C₁₋₆alkyl, —O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl),—O(aryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl), —N(C₀₋₆alkyl)(C₃₋₇cycloalkyl),—N(C₀₋₆alkyl)(aryl) substituents;

R⁸ is —C₁₋₆alkyl, —C₃₋₇cycloalkyl, heteroaryl, or aryl; optionallysubstituted with 1-5 independent halogen, —CN, —C₁₋₆alkyl,—O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl), —O(aryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl),—N(C₀₋₆alkyl)(C₃₋₇cycloalkyl), —N(C₀₋₆alkyl)(aryl) substituents;

B is —C₀₋₄alkyl, —C₀₋₂alkyl-SO—C₀₋₂alkyl-, —C₀₋₂alkyl-SO₂—C₀₋₂alkyl-,—C₀₋₂alkyl-CO—C₀₋₂alkyl-, —C₀₋₂alkyl-NR¹⁰CO—C₀₋₂alkyl-,—C₀₋₂alkyl-NR¹⁰SO₂—C₀₋₂alkyl- or -heteroC₀₋₄alkyl;

R⁹ and R¹⁰ each independently is —C₀₋₆alkyl, —C₃₋₇cycloalkyl,heteroaryl, or aryl; any of which is optionally substituted with 1-5independent halogen, —CN, —C₁₋₆alkyl, —O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl),—O(aryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl), —N(C₀₋₆alkyl)(C₃₋₇cycloalkyl),—N(C₀₋₆alkyl)(aryl) substituents;

Z is —C₃₋₇cycloalkyl, -heteroC₃₋₇cycloalkyl, —C₀₋₆alkylaryl, or—C₀₋₆alkylheteroaryl optionally substituted with 1-7 independenthalogen, —CN, NO₂, —C₁₋₆alkyl, —C₁₋₆alkenyl, —C₁₋₆alkynyl, —OR¹, —NR¹R²,—C(═NR¹)NR²R³, —N(═NR¹)NR²R³, —NR¹COR², —NR¹CO₂R², —NR¹SO₂R⁴,—NR¹CONR²R³ , —SR⁴, —SOR⁴, —SO₂R⁴, —SO₂NR¹R², —COR¹, —CO₂R¹, —CONR¹R²,—C(═NR¹)R², or —C(═NOR¹)R² substituents;

one of W and Z is optionally absent;

R¹¹ and R¹² is each independently halogen, —C₀₋₆alkyl, —C₀₋₆alkoxyl, ═O,═N(C₀₋₄alkyl),or —N(C₀₋₄alkyl)(C₀₋₄alkyl); and

any alkyl optionally substituted with 1-5 independent halogensubstituents, and any N may be an N-oxide.

As used herein, “alkyl” as well as other groups having the prefix “alk”such as, for example, alkoxy, alkanoyl, alkenyl, alkynyl and the like,means carbon chains which may be linear or branched or combinationsthereof. Examples of alkyl groups include methyl, ethyl, propyl,isopropyl, butyl, sec- and tert-butyl, pentyl, hexyl, heptyl and thelike. “Alkenyl”, “alkynyl” and other like terms include carbon chainscontaining at least one unsaturated C—C bond.

The term “cycloalkyl” means carbocycles containing no heteroatoms, andincludes mono-, bi- and tricyclic saturated carbocycles, as well asfused ring systems. Such fused ring systems can include one ring that ispartially or fully unsaturated such as a benzene ring to form fused ringsystems such as benzofused carbocycles. Cycloalkyl includes such fusedring systems as spirofused ring systems. Examples of cycloalkyl includecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, decahydronaphthalene,adamantane, indanyl, indenyl, fluorenyl, 1,2,3,4-tetrahydronaphalene andthe like. Similarly, “cycloalkenyl” means carbocycles containing noheteroatoms and at least one non-aromatic C—C double bond, and includemono-, bi- and tricyclic partially saturated carbocycles, as well asbenzofused cycloalkenes. Examples of cycloalkenyl include cyclohexenyl,indenyl, and the like.

The term “aryl” means an aromatic substituent which is a single ring ormultiple rings fused together. When formed of multiple rings, at leastone of the constituent rings is aromatic. The preferred arylsubstituents are phenyl and naphthyl groups.

The term “cycloalkyloxy” unless specifically stated otherwise includes acycloalkyl group connected by a short C₁₋₂alkyl length to the oxyconnecting atom.

The term “C₀₋₆alkyl” includes alkyls containing 6, 5, 4, 3, 2, 1, or nocarbon atoms. An alkyl with no carbon atoms is a hydrogen atomsubstituent when the alkyl is a terminal group and is a direct bond whenthe alkyl is a bridging group.

The term “hetero” unless specifically stated otherwise includes one ormore O, S, or N atoms. For example, heterocycloalkyl and heteroarylinclude ring systems that contain one or more O, S, or N atoms in thering, including mixtures of such atoms. The hetero atoms replace ringcarbon atoms. Thus, for example, a heterocycloC₅alkyl is a five-memberring containing from 4 to no carbon atoms. Examples of heteroarylsinclude pyridinyl, quinolinyl, isoquinolinyl, pyridazinyl, pyrimidinyl,pyrazinyl, quinoxalinyl, furyl, benzofuryl, dibenzofuryl, thienyl,benzthienyl, pyrrolyl, indolyl, pyrazolyl, indazolyl, oxazolyl,benzoxazolyl, isoxazolyl, thiazolyl, benzothiazolyl, isothiazolyl,imidazolyl, benzimidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, andtetrazolyl. Examples of heterocycloalkyls include azetidinyl,pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl,imidazolinyl, pyrolidin-2-one, piperidin-2-one, and thiomorpholinyl.

The term “heteroC₀₋₄alkyl” means a heteroalkyl containing 3, 2, 1, or nocarbon atoms. However, at least one heteroatom must be present. Thus, asan example, a heteroC₀₋₄alkyl having no carbon atoms but one N atomwould be a —NH— if a bridging group and a —NH₂ if a terminal group.Analogous bridging or terminal groups are clear for an O or Sheteroatom.

The term “amine” unless specifically stated otherwise includes primary,secondary and tertiary amines substituted with C₀₋₆alkyl.

The term “carbonyl” unless specifically stated otherwise includes aC₀₋₆alkyl substituent group when the carbonyl is terminal.

The term “halogen” includes fluorine, chlorine, bromine and iodineatoms.

The term “optionally substituted” is intended to include bothsubstituted and unsubstituted. Thus, for example, optionally substitutedaryl could represent a pentafluorophenyl or a phenyl ring. Further,optionally substituted multiple moieties such as, for example, alkylarylare intended to mean that the aryl and the aryl groups are optionallysubstituted. If only one of the multiple moieties is optionallysubstituted then it will be specifically recited such as “an alkylaryl,the aryl optionally substituted with halogen or hydroxyl.”Compoundsdescribed herein contain one or more double bonds and may thus give riseto cis/trans isomers as well as other conformational isomers. Thepresent invention includes all such possible isomers as well as mixturesof such isomers.

Compounds described herein can contain one or more asymmetric centersand may thus give rise to diastereomers and optical isomers. The presentinvention includes all such possible diastereomers as well as theirracemic mixtures, their substantially pure resolved enantiomers, allpossible geometric isomers, and pharmaceutically acceptable saltsthereof. The above Formula I is shown without a definitivestereochemistry at certain positions. The present invention includes allstereoisomers of Formula I and pharmaceutically acceptable saltsthereof. Further, mixtures of stereoisomers as well as isolated specificstereoisomers are also included. During the course of the syntheticprocedures used to prepare such compounds, or in using racemization orepimerization procedures known to those skilled in the art, the productsof such procedures can be a mixture of stereoisomers.

The term “pharmaceutically acceptable salts” refers to salts preparedfrom pharmaceutically acceptable non-toxic bases or acids. When thecompound of the present invention is acidic, its corresponding salt canbe conveniently prepared from pharmaceutically acceptable non-toxicbases, including inorganic bases and organic bases. Salts derived fromsuch inorganic bases include aluminum, ammonium, calcium, copper (ic andous), ferric, ferrous, lithium, magnesium, manganese (ic and ous),potassium, sodium, zinc and the like salts. Particularly preferred arethe ammonium, calcium, magnesium, potassium and sodium salts. Saltsderived from pharmaceutically acceptable organic non-toxic bases includesalts of primary, secondary, and tertiary amines, as well as cyclicamines and substituted amines such as naturally occurring andsynthesized substituted amines. Other pharmaceutically acceptableorganic non-toxic bases from which salts can be formed include ionexchange resins such as, for example, arginine, betaine, caffeine,choline, N,N′-dibenzylethylenediamine, diethylamine,2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine,ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine,glucosamine, histidine, hydrabamine, isopropylamine, lysine,methylglucamnine, morpholine, piperazine, piperidine, polyamine resins,procaine, purines, theobromine, triethylamine, trimethylamine,tripropylamine, tromethamine and the like.

When the compound of the present invention is basic, its correspondingsalt can be conveniently prepared from pharmaceutically acceptablenon-toxic acids, including inorganic and organic acids. Such acidsinclude, for example, acetic, benzenesulfonic, benzoic, camphorsulfonic,citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic,hydrochloric, isethionic, lactic, maleic, malic, mandelic,methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric,succinic, sulfuric, tartaric, p-toluenesulfonic acid and the like.Particularly preferred are citric, hydrobromic, hydrochloric, maleic,phosphoric, sulfuric, and tartaric acids.

The pharmaceutical compositions of the present invention comprise acompound represented by Formula I (or pharmaceutically acceptable saltsthereof) as an active ingredient, a pharmaceutically acceptable carrierand optionally other therapeutic ingredients or adjuvants. Suchadditional therapeutic ingredients include, for example, i) opiateagonists or antagonists, ii) calcium channel antagonists, iii) 5HTreceptor agonists or antagonists iv) sodium channel antagonists, v) NMDAreceptor agonists or antagonists, vi) COX-2 selective inhibitors, vii)NK1 antagonists, viii) non-steroidal anti-inflammatory drugs (“NSAID”),ix) GABA-A receptor modulators, x) dopamine agonists or antagonists, xi)selective serotonin reuptake inhibitors (“SSRI”) and/or selectiveserotonin and norepinephrine reuptake inhibitors (“SSNRI”), xii)tricyclic antidepressant drugs, xiv) norepinephrine modulators, xv)L-DOPA, xvi) buspirone, xvii) lithium, xviii) valproate, ixx) neurontin(gabapentin), xx) olanzapine, xxi) nicotinic agonists or antagonistsincluding nicotine, xxii) muscarinic agonists or antagonists, xxiii)heroin substituting drugs such as methadone, levo-alpha-acetylmethadol,buprenorphine and naltrexone, and xxiv) disulfiram and acamprosate. Thecompositions include compositions suitable for oral, rectal, topical,and parenteral (including subcutaneous, intramuscular, and intravenous)administration, although the most suitable route in any given case willdepend on the particular host, and nature and severity of the conditionsfor which the active ingredient is being administered. Thepharmaceutical compositions may be conveniently presented in unit dosageform and prepared by any of the methods well known in the art ofpharmacy.

Creams, ointments, jellies, solutions, or suspensions containing thecompound of Formula I can be employed for topical use. Mouth washes andgargles are included within the scope of topical use for the purposes ofthis invention.

Dosage levels from about 0.01 mg/kg to about 140 mg/kg of body weightper day are useful in the treatment of psychiatric and mood disorderssuch as, for example, schizophrenia, anxiety, depression, panic, bipolardisorders, and circadian disorders, as well as being useful in thetreatment of pain which are responsive to mGluR5 inhibition, oralternatively about 0.5 mg to about 7 g per patient per day. Forexample, schizophrenia, anxiety, depression, and panic may beeffectively treated by the administration of from about 0.01 mg to 75 mgof the compound per kilogram of body weight per day, or alternativelyabout 0.5 mg to about 3.5 g per patient per day. Pain may be effectivelytreated by the administration of from about 0.01 mg to 125 mg of thecompound per kilogram of body weight per day, or alternatively about 0.5mg to about 5.5 g per patient per day. Further, it is understood thatthe mGluR5 inhibiting compounds of this invention can be administered atprophylactically effective dosage levels to prevent the above-recitedconditions.

The amount of active ingredient that may be combined with the carriermaterials to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration. For example, aformulation intended for the oral administration to humans mayconveniently contain from about 0.5 mg to about 5 g of active agent,compounded with an appropriate and convenient amount of carrier materialwhich may vary from about 5 to about 95 percent of the totalcomposition. Unit dosage forms will generally contain between from about1 mg to about 1000 mg of the active ingredient, typically 25 mg, 50 mg,100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg or 1000 mg.

It is understood, however, that the specific dose level for anyparticular patient will depend upon a variety of factors including theage, body weight, general health, sex, diet, time of administration,route of administration, rate of excretion, drug combination and theseverity of the particular disease undergoing therapy.

In practice, the compounds represented by Formula I, or pharmaceuticallyacceptable salts thereof, of this invention can be combined as theactive ingredient in intimate admixture with a pharmaceutical carrieraccording to conventional pharmaceutical compounding techniques. Thecarrier may take a wide variety of forms depending on the form ofpreparation desired for administration, e.g., oral or parenteral(including intravenous). Thus, the pharmaceutical compositions of thepresent invention can be presented as discrete units suitable for oraladministration such as capsules, cachets or tablets each containing apredetermined amount of the active ingredient. Further, the compositionscan be presented as a powder, as granules, as a solution, as asuspension in an aqueous liquid, as a non-aqueous liquid, as anoil-in-water emulsion or as a water-in-oil liquid emulsion. In additionto the common dosage forms set out above, the compound represented byFormula I, or pharmaceutically acceptable salts thereof, may also beadministered by controlled release means and/or delivery devices. Thecompositions may be prepared by any of the methods of pharmacy. Ingeneral, such methods include a step of bringing into association theactive ingredient with the carrier that constitutes one or morenecessary ingredients. In general, the compositions are prepared byuniformly and intimately admixing the active ingredient with liquidcarriers or finely divided solid carriers or both. The product can thenbe conveniently shaped into the desired presentation.

Thus, the pharmaceutical compositions of this invention may include apharmaceutically acceptable carrier and a compound or a pharmaceuticallyacceptable salt of Formula I. The compounds of Formula I, orpharmaceutically acceptable salts thereof, can also be included inpharmaceutical compositions in combination with one or more othertherapeutically active compounds.

The pharmaceutical carrier employed can be, for example, a solid,liquid, or gas. Examples of solid carriers include lactose, terra alba,sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, andstearic acid. Examples of liquid carriers are sugar syrup, peanut oil,olive oil, and water. Examples of gaseous carriers include carbondioxide and nitrogen.

In preparing the compositions for oral dosage form, any convenientpharmaceutical media may be employed. For example, water, glycols, oils,alcohols, flavoring agents, preservatives, coloring agents and the likemay be used to form oral liquid preparations such as suspensions,elixirs and solutions; while carriers such as starches, sugars,microcrystalline cellulose, diluents, granulating agents, lubricants,binders, disintegrating agents, and the like may be used to form oralsolid preparations such as powders, capsules and tablets. Because oftheir ease of administration, tablets and capsules are the preferredoral dosage units whereby solid pharmaceutical carriers are employed.Optionally, tablets may be coated by standard aqueous or nonaqueoustechniques

A tablet containing the composition of this invention may be prepared bycompression or molding, optionally with one or more accessoryingredients or adjuvants. Compressed tablets may be prepared bycompressing, in a suitable machine, the active ingredient in afree-flowing form such as powder or granules, optionally mixed with abinder, lubricant, inert diluent, surface active or dispersing agent.Molded tablets may be made by molding in a suitable machine, a mixtureof the powdered compound moistened with an inert liquid diluent. Eachtablet preferably contains from about 0.1 mg to about 500 mg of theactive ingredient and each cachet or capsule preferably containing fromabout 0.1 mg to about 500 mg of the active ingredient. Thus, a tablet,cachet, or capsule conveniently contains 0.1 mg, 1 mg, 5 mg, 25 mg, 50mg, 100 mg, 200 mg, 300 mg, 400 mg, or 500 mg of the active ingredienttaken one or two tablets, cachets, or capsules, once, twice, or threetimes daily.

Pharmaceutical compositions of the present invention suitable forparenteral administration may be prepared as solutions or suspensions ofthe active compounds in water. A suitable surfactant can be includedsuch as, for example, hydroxypropylcellulose. Dispersions can also beprepared in glycerol, liquid polyethylene glycols, and mixtures thereofin oils. Further, a preservative can be included to prevent thedetrimental growth of microorganisms.

Pharmaceutical compositions of the present invention suitable forinjectable use include sterile aqueous solutions or dispersions.Furthermore, the compositions can be in the form of sterile powders forthe extemporaneous preparation of such sterile injectable solutions ordispersions. In all cases, the final injectable form must be sterile andmust be effectively fluid for easy syringability. The pharmaceuticalcompositions must be stable under the conditions of manufacture andstorage; thus, preferably should be preserved against the contaminatingaction of microorganisms such as bacteria and fungi. The carrier can bea solvent or dispersion medium containing, for example, water, ethanol,polyol (e.g. glycerol, propylene glycol and liquid polyethylene glycol),vegetable oils, and suitable mixtures thereof.

Pharmaceutical compositions of the present invention can be in a formsuitable for topical use such as, for example, an aerosol, cream,ointment, lotion, dusting powder, or the like. Further, the compositionscan be in a form suitable for use in transdermal devices. Theseformulations may be prepared, utilizing a compound represented byFormula I of this invention, or pharmaceutically acceptable saltsthereof, via conventional processing methods. As an example, a cream orointment is prepared by mixing hydrophilic material and water, togetherwith about 5 wt % to about 10 wt % of the compound, to produce a creamor ointment having a desired consistency.

Pharmaceutical compositions of this invention can be in a form suitablefor rectal administration wherein the carrier is a solid. It ispreferable that the mixture forms unit dose suppositories. Suitablecarriers include cocoa butter and other materials commonly used in theart. The suppositories may be conveniently formed by first admixing thecomposition with the softened or melted carrier(s) followed by chillingand shaping in moulds.

In addition to the aforementioned carrier ingredients, thepharmaceutical formulations described above may include, as appropriate,one or more additional carrier ingredients such as diluents, buffers,flavoring agents, binders, surface-active agents, thickeners,lubricants, preservatives (including anti-oxidants) and the like.Furthermore, other adjuvants can be included to render the formulationisotonic with the blood of the intended recipient. Compositionscontaining a compound described by Formula I, or pharmaceuticallyacceptable salts thereof, may also be prepared in powder or liquidconcentrate form.

The compounds and pharmaceutical compositions of this invention havebeen found to exhibit biological activity as mGluR5 inhibitors.Accordingly, another aspect of the invention is the treatment in mammalsof, for example, schizophrenia, anxiety, depression, panic, bipolardisorders, circadian rhythm and sleep disorders, pain, Parkinson'sdisease, cognitive dysfunction, epilepsy, obesity, drug addiction, drugabuse and drug withdrawal—maladies that are amenable to ameliorationthrough inhibition of mGluR5—by the administration of an effectiveamount of the compounds of this invention. The term “mammals” includeshumans, as well as other animals such as, for example, dogs, cats,horses, pigs, and cattle. Accordingly, it is understood that thetreatment of mammals other than humans is the treatment of clinicalcorrelating afflictions to those above recited examples that are humanafflictions.

Further, as described above, the compound of this invention can beutilized in combination with other therapeutic compounds. In particular,the combinations of the mGluR5 inhibiting compound of this invention canbe advantageously used in combination with i) opiate agonists orantagonists, ii) calcium channel antagonists, iii) 5HT receptor agonistsor antagonists iv) sodium channel antagonists, v) NMDA receptor agonistsor antagonists, vi) COX-2 selective inhibitors, vii) NK1 antagonists,viii) non-steroidal anti-inflammatory drugs (“NSAID”), ix) GABA-Areceptor modulators, x) dopamine agonists or antagonists, xi) selectiveserotonin reuptake inhibitors (“SSRI”) and/or selective serotonin andnorepinephrine reuptake inhibitors (“SSNRI”), xii) tricyclicantidepressant drugs, xiii) norepinephrine modulators, xiv) L-DOPA, xv)buspirone, xvi) lithium, xvii) valproate, xviii) neurontin (gabapentin),xix) olanzapine, xx) nicotinic agonists or antagonists includingnicotine, xxi) muscarinic agonists or antagonists, xxii) heroinsubstituting drugs such as methadone, levo-alpha-acetylmethadol,buprenorphine and naltrexone, and xxiii) disulfiram and acamprosate.

The abbreviations used herein have the following tabulated meanings.Abbreviations not tabulated below have their meanings as commonly usedunless specifically stated otherwise. Ac acetyl AIBN2,2′-azobis(isobutyronitrile) BINAP 1,1′-bi-2-naphthol Bn benzyl CAMPcyclic adenosine-3′,5′-monophosphate DAST (diethylamino)sulfurtrifluoride DEAD diethyl azodicarboxylate DBU1,8-diazabicyclo[5.4.0]undec-7-ene DIBAL diisobutylaluminum hydride DMAP4-(dimethylamino)pyridine DMF N,N-dimethylformamide Dppf1,1′-bis(diphenylphosphino)-ferrocene EDCI1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride Et₃Ntriethylamine GST glutathione transferase HMDS hexamethyldisilazide LDAlithium diisopropylamide m-CPBA metachloroperbenzoic acid MMPPmonoperoxyphthalic acid MPPM monoperoxyphthalic acid, magnesium salt6H₂O Ms methanesulfonyl = mesyl = SO₂Me Ms0 methanesulfonate = mesylateNBS N-bromo succinimide NSAID non-steroidal anti-inflammatory drug o-Tolortho-tolyl OXONE ® 2KHSO₅.KHSO₄.K₂SO₄ PCC pyridinium chlorochromatePd₂(dba)₃ Bis(dibenzylideneacetone)palladium(0) PDC pyridiniumdichromate PDE Phosphodiesterase Ph Phenyl Phe Benzenediyl PMBpara-methoxybenzyl Pye Pyridinediyl r.t. room temperature Rac. RacemicSAM aminosulfonyl or sulfonamide or SO₂NH₂ SEM2-(trimethylsilyl)ethoxymethoxy SPA scintillation proximity assay TBAFtetra-n-butylammonium fluoride Th 2- or 3-thienyl TFA trifluoroaceticacid TFAA trifluoroacetic acid anhydride THF Tetrahydrofuran ThiThiophenediyl TLC thin layer chromatography TMS-CN trimethylsilylcyanide TMSI trimethylsilyl iodide Tz 1H(or 2H)-tetrazol-5-yl XANTPHOS4,5-Bis-diphenylphosphanyl-9,9-dimethyl-9H- xanthene C₃H₅ Allyl

Alkyl Group Abbreviations Me = Methyl Et = ethyl n-Pr = normal propyli-Pr = isopropyl n-Bu = normal butyl i-Bu = isobutyl s-Bu = secondarybutyl t-Bu = tertiary butyl c-Pr = cyclopropyl c-Bu = cyclobutyl c-Pen =cyclopentyl c-Hex = cyclohexyl

Assays Demonstrating Biological Activity

The compounds of this invention were tested against the hmGluR5areceptor stably expressed in mouse fibroblast Ltk³¹ cells (thehmGluR5a/L38-20 cell line) and activity was detected by changes in[Ca++]_(i), measured using the fluorescent Ca++-sensitive dye, fura-2.InsP assays were performed in mouse fibroblast Ltk⁻ cells (LM5a cellline) stably expressing hmGluR5a. The assays described in InternationalPatent Publication WO 0116121 can be used.

Calcium Flux Assay

The activity of compounds was examined against the hmGluR5a receptorstably expressed in mouse fibroblast Ltk⁻ cells (the hmGluR5a/L38 cellline). See generally Daggett et al., Neuropharmacology 34:871-886(1995). Receptor activity was detected by changes in intracellularcalcium ([Ca²⁺]_(i)) measured using the fluorescent calcium-sensitivedye, fura-2. The hmGluR5a/L38-20 cells were plated onto 96-well plates,and loaded with 3 μM fura-2 for 1 h. Unincorporated dye was washed fromthe cells, and the cell plate was transferred to a 96-channelfluorimeter (SIBIA-SAIC, La Jolla, Calif.) which is integrated into afully automated plate handling and liquid delivery system. Cells wereexcited at 350 and 385 nm with a xenon source combined with opticalfilters. Emitted light was collected from the sample through a dichroicmirror and a 510 nm interference filter and directed into a cooled CCDcamera (Princeton Instruments). Image pairs were captured approximatelyevery Is, and ratio images were generated after background subtraction.After a basal reading of 20s, an EC₈₀ concentration of glutamate (10 μM)was added to the well, and the response evaluated for another 60s. Theglutamate-evoked increase in [Ca¹]_(i) in the presence of the screeningcompound was compared to the response of glutamate alone (the positivecontrol).

Phosphatidylinositol Hydrolysis (PI) Assays

Inositolphosphate assays were performed as described by Berridge et al.[Berridge et al, Biochem. J. 206: 587-5950 (1982); and Nakajima et al.,J. Biol. Chem. 267:2437-2442 (1992)) with slight modifications. Mousefibroblast Ltk cells expressing hmGluR5 (hmGluR5/L38-20 cells) wereseeded in 24-well plates at a density of 8×105cells/well. One μCi of[³H)-inositol (Amersham PT6-271; Arlington Heights, El.; specificactivity=17.7 Ci/mmol) was added to each well and incubated for 16 h at37° C. Cells were washed twice and incubated for 45 min in 0.5 mL ofstandard Hepes buffered saline buffer (HBS; 125 mM NaCl, 5 mM KCI, 0.62mM MgSO₄, 1.8 mM CaCl₂, 20 mM HEPES, 6 mM glucose, pH to 7.4). The cellswere washed with HBS containing 10 mM LiCl, and 400 μL buffer added toeach well. Cells were incubated at 37° C. for 20 min. For testing, 50 μLof 10× compounds used in the practice of the invention (made in HBS/LiCl(100 mM)) was added and incubated for 10 minutes. Cells were activatedby the addition of 10 μM glutamate, and the plates left for 1 hour at37° C. The incubations were terminated by the addition of 1 mL ice-coldmethanol to each well. In order to isolate inositol phosphates (IPs),the cells were scraped from wells, and placed in numbered glass testtubes. One mL of chloroform was added to each tube, the tubes weremixed, and the phases separated by centrifugation. IPs were separated onDowex anion exchange columns (AG 1-X8 100-200 mesh formate form). Theupper aqueous layer (750 μL) was added to the Dowex columns, and thecolumns eluted with 3 mL of distilled water. The eluents were discarded,and the columns were washed with 10 mLs of 60 mM ammonium formate/5 mMBorax, which was also discarded as waste. Finally, the columns wereeluted with 4 mL of 800 mM ammonium formate/0.1 M formic acid, and thesamples collected in scintillation vials. Scintillant was added to eachvial, and the vials shaken, and counted in a scintillation counter after2 hours. Phosphatidylinositol hydrolysis in cells treated with certainexemplary compounds was compared to phosphatidylinositol hydrolysis incells treated with the agonist alone in the absence of compound.

The compounds of this application have mGluR5 inhibitory activity asshown by IC₅₀ values of less than 10 μM in the calcium flux assay orinhibition at a concentration of 100 μM in the PI assay. Preferably, thecompounds should have IC₅₀ values of less than 1 μM in the calcium fluxassay and IC₅₀ values of less than 10 μM in the PI assay. Even morepreferably, the compounds should have IC₅₀ values of less than 500 nM inthe calcium flux assay and IC₅₀ values of less than 1 μM in the PI assayExamples I to 6 have mGluR5 inhibitory activity as shown by inhibitionat 10 μM or less in the calcium flux assay or inhibition at 100 μM orless in the PI assay.

The examples that follow are intended as an illustration of certainpreferred embodiments of the invention and no limitation of theinvention is implied.

Unless specifically stated otherwise, the experimental procedures wereperformed under the following conditions. All operations were carriedout at room or ambient temperature—that is, at a temperature in therange of 18-25° C. Evaporation of solvent was carried out using a rotaryevaporator under reduced pressure (600-4000 pascals: 4.5-30 mm. Hg) witha bath temperature of up to 60° C. The course of reactions was followedby thin layer chromatography (TLC) and reaction times are given forillustration only. The structure and purity of all final products wereassured by at least one of the following techniques: TLC, massspectrometry, nuclear magnetic resonance (NMR) spectrometry ormicroanalytical data. When given, yields are for illustration only. Whengiven, NMR data is in the form of delta (δ) values for major diagnosticprotons, given in parts per million (ppm) relative to tetramethylsilane(TMS) as internal standard, determined at 300 MHz, 400 MHz or 500 MHzusing the indicated solvent. Conventional abbreviations used for signalshape are: s. singlet; d. doublet; t. triplet; m. multiplet; br. broad;etc. In addition, “Ar” signifies an aromatic signal. Chemical symbolshave their usual meanings; the following abbreviations are used: v(volume), w (weight), b.p. (boiling point), m.p. (melting point), L(liter(s)), mL (milliliters), g (gram(s)), mg (milligrams(s)), mol(moles), mmol (millimoles), eq (equivalent(s)).

Methods of Synthesis

Compounds of the present invention can be prepared according to thefollowing methods. The substituents are the same as in Formula (I)except where defined otherwise, or apparent to one in the art.

In accordance with another embodiment of the present invention, thereare provided methods for the preparation of heteroaryl-substitutedimidazole compounds as described above. For example, many of theheterocyclic compounds described above can be prepared using syntheticchemistry techniques well known in the art (see ComprehensiveHeterocyclic Chemistry, Katritzky, A. R. and Rees, C. W. eds., PergamonPress, Oxford, 1984) from a heteoaryl-substituted imidazole of Formula(I).

In Schemes 1 to 5 below, X and Y are as defined above. Other variablesare understood by one in the art by the context in which they are used.

Thus in Scheme 1, a suitably substituted imidazole containing afunctional group A ,which is capable of undergoing a metal-catalyzedcross-coupling reaction, such as a halogen or trifluoromethanesulfonateand the like (prepared using synthetic chemistry techniques well knownin the art) may be coupled with a species X substituted with a group B.B may be a metalloid such as B(OR)₂, BiLn or related species and thereaction may be promoted with stoichiometric or catalytic amounts ofmetal salts such as Cu(OAc)₂, CuI, [Cu(OH)TMEDA]₂Cl₂ or CuOTf and thelike. Typically a base (e.g. pyridine, NEt₃, Cs₂CO₃, K₃PO₄, K₂CO₃ etc.)will also be present and the reaction carried out in a suitable solvent(e.g. DCM, THF, DME, dioxane, toluene, MeCN, DMF, H₂O etc.).Additionally, molecular sieves may be used as a cocatalyst and anatmosphere of oxygen may be required. The cross-coupling reaction may becarried out at rt or heated to a temperature between about 30° C. to150° C. The reaction mixture is then maintained at a suitabletemperature for a time in the range of about 4 up to 72 h, with 18 htypically being sufficient (see for example Lam, P. Y. S.; Clark, C. G.;Saubern, S.; Adams, J.; Winters, M. P.; Cham, D. M. T.; Combs, A.Tetrahedron Lett. 1998, 39, 2941-2944 and Kiyomori, A.; Marcoux, J. F.;Buchwald, S. L. Tetrahedron Lett. 1999, 40, 2657-2660 and Collman, J.P.; Zhong, M. Org. Lett. 2000, 2, 9, 1233-1236). The product from thereaction can be isolated and purified employing standard techniques,such as solvent extraction, chromatography, crystallization,distillation and the like.

In another embodiment of the present invention when B is a good leavinggroup such as F, and X is electron deficient or has one or more electronwithdrawing substituents (e.g. NO₂, CN), the coupling reaction may beeffected thermally in a temperature range of about 60° C. up to about250° C. Typically, this reaction is carried out in the presence of base(e.g. pyridine, NEt₃, Cs₂CO₃, K₂CO₃ etc.) in a suitable solvent, such asDMSO, DMF, DMA H₂O and the like, and takes from 1 h up to about 72 hwith 18 h typically being sufficient (see for example Davey, D. D.;Erhardt, P. W.; Cantor, E. H.; Greenberg, S. S.; Ingebretsen, W. R.;Wiggins; J. Med. Chem. 1991, 34, 9, 2671-2677).

In turn the derivatized imidazole is reacted with a moiety Y undermetal-catalyzed cross-coupling conditions (Scheme 2)

where E is a metallic or metalloid species such as B(OR)₂, Li, MgHal,SnR₃, ZnHal, SiR₃ and the like which is capable of undergoing ametal-catalyzed cross-coupling reaction. The coupling may be promoted bya homogeneous catalyst such as Pd(PPh₃)₄, or by a heterogeneous catalystsuch as Pd on carbon in a suitable solvent (e.g. TIF, DME, toluene,MeCN, DMF, H₂O etc.). Typically a base, such as K₂CO₃, NEt₃, and thelike, will also be present in the reaction mixture. Other promoters mayalso be used such as CsF. The reaction mixture is maintained at rt, orheated to a temperature between 30° C. to 150° C. The reaction mixtureis then maintained at a suitable temperature for a time in the range ofabout 4 up to 48 h, with about 18 h typically being sufficient (see forexample Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457-2483). Theproduct from the reaction can be isolated and purified employingstandard techniques, such as solvent extraction, chromatography,crystallization, distillation and the like.

Another Embodiment of the Present Invention is Illustrated in Scheme 3

Thus a suitably substituted imidazole containing a functional group A,which is capable of undergoing a metal-catalyzed cross-couplingreaction, such as a halogen or trifluoromethanesulfonate and the like(prepared using synthetic chemistry techniques well known in the art)may be coupled with a species Y substituted with a group E where E is ametallic or metalloid species such as B(OR)₂, Li, MgHal, SnR₃, ZnHal,SiR₃ and the like. The coupling may be promoted by a homogeneouscatalyst such as Pd(PPh₃)₄, or by a heterogeneous catalyst such as Pd oncarbon in a suitable solvent (e.g. THF, DME, toluene, MeCN, DMF, H₂Oetc.). Typically a base, such as K₂CO₃, NEt₃, and the like, will also bepresent in the reaction mixture. Other promoters may also be used suchas CsF. The reaction mixture is maintained at rt, or heated to atemperature between about 30° C. to 150° C. The reaction mixture is thenmaintained at a suitable temperature for a time in the range of about 4h up to 48 h, with about 18 h typically being sufficient (see forexample Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457-2483 orNegishi, E., Liu, F., Palladium or Nickel catalyzed Cross-coupling withOrganometals Containing Zinc, Magnesium, Aluminium and Zirconium inMetal-catalyzed Cross-coupling Reactions Diederich, F.; Stang, P. J.Eds. Wiley, Weinheim, Germany, 1998; pp 1-42). The product from thereaction can be isolated and purified employing standard techniques,such as solvent extraction, chromatography, crystallization,distillation and the like.

Another Embodiment of the Present Invention is Illustrated in Scheme 4

Thus a suitably substituted species Y containing a pendant aldehydegroup (prepared using synthetic chemistry techniques well known in theart) may be converted to a substituted imidazole in a two stepprocedure. First, the aldehyde is converted to an intermediatesubstituted oxazole using tosylmethylisocyanide in a suitable solvent(e.g. THF, EtOH, dioxane, DCM, toluene etc.) in the presence of asuitable base (such as NaH, KOtBu, KCN, K₂CO₃ etc.). The reactionmixture is then maintained at rt, or heated to a temperature betweenabout 30° C. to 100° C. The reaction mixture is then maintained at therequired temperature for a time in the range of about 2 h up to 48 h,with about 6 h typically being sufficient. The intermediate oxazole isthen heated with ammonia in a suitable solvent (e.g. THF, MeOH, DCM,toluene, dioxane etc.). The reaction mixture is then maintained atambient temperature, or heated to a temperature anywhere between 30° C.to 150° C. The reaction mixture is then stirred for a time in the rangeof about 2 up to 48 h, with about 24 h typically being sufficient. Theproduct from the reaction can be isolated and purified employingstandard techniques, such as solvent extraction, chromatography,crystallization, distillation and the like (see for example Wang, F.;Schwabacher, A. W. Tetrahedron. Lett. 1999, 40, 4779-4782).

As shown in Scheme 5, the imidazole may then be coupled with a ringsystem X substituted with a functional group B.

B may be a metalloid species such as B(OR)₂, BiLn or the like and thereaction may be promoted with stoichiometric or catalytic amounts ofmetal salts such as Cu(OAc)₂, CuI, [Cu(OH)TMEDA]₂Cl₂ or CuOTf and thelike. Typically, a base (e.g. pyridine, NEt₃, Cs₂CO₃, K₃PO₄, K₂CO₃ etc.)will also be present and the reaction carried out in a suitable solvent(e.g. DCM, THF, DME, dioxane, toluene, MeCN, DMF, H₂O etc.).Additionally, molecular sieves may be used as a cocatalyst and anatmosphere of oxygen may be required. The cross-coupling reaction may becarried out at ambient temperature or heated to a temperature anywherebetween 30° C. to 150° C. The reaction mixture is then maintained at asuitable temperature for a time in the range of about 4 up to 72 h, with18 h typically being sufficient (see for example Lam, P. Y. S.; Clark,C. G.; Saubern, S.; Adams, J.; Winters, M. P.; Cham, D. M. T.; Combs, A.Tetrahedron Lett. 1998, 39, 2941-2944 and Kiyomori, A.; Marcoux, J. F.;Buchwald, S. L. Tetrahedron Lett. 1999, 40, 2657-2660 and Collman, J.P.; Zhong, M. Org. Lett. 2000, 2, 9, 1233-1236). The product from thereaction can be isolated and purified employing standard techniques,such as solvent extraction, chromatography, crystallization,distillation and the like.

Alternatively, B may be a leaving group capable of undergoing ametal-catalyzed cross-coupling reaction such as a halogen ortrifluoromethanesulfonate and the like. Typically, the reaction iscarried out using catalytic amounts of a copper (I) salt together with adi-amine ligand and in the presence of a suitable base (e.g. K₃PO₄,Cs₂CO₃, K₂CO₃ etc.) in a suitable solvent, such as dioxane, DMSO, DMA,DMF (see for example Klapars, A.; Antilla, J. C.; Huang, X.; Buchwald,S. L J. Am. Chem Soc. 2001, 123(31); 7727-7729).

Additionally, when B is a good aryl leaving group such as F, and X iselectron deficient or has one or more electron withdrawing substituents(e.g. NO₂, CN), the coupling reaction may be effected thermally in atemperature range of about 60° C. up to about 250° C. Typically, thisreaction is carried out in the presence of base (e.g. pyridine, NEt₃,Cs₂CO₃, K₂CO₃ etc.) in a suitable solvent, such as DMSO, DMF, DMA H₂Oand the like, and takes from 1 h up to about 72 h with 18 h typicallybeing sufficient (see for example Davey, D. D.; Erhardt, P. W.; Cantor,E. H.; Greenberg, S. S.; Ingebretsen, W. R.; Wiggins; J. Med. Chem.1991, 34, 9, 2671-2677).

In the schemes above, ring systems X and/or Y may already contain apendant ring W and/or Z. However, if required, ring systems W and/or Zmay be appended to X and/or Y respectively where G and/or J arefunctional groups capable of undergoing a metal catalyzed-cross coupling(such as halogen, trifluoromethane-sulfonate, B(OR)₂, ZnX, SnR₃, and thelike—Scheme 6 below). Ring systems W and Z are substituted with groupsP, Q, S and T which may be for example, halogen,trifluoromethanesulfonate, B(OR)₂, ZnX, SnR₃, and the like. Typically, atransition metal catalyst such as Pd(PPh₃)₄, Pd(PPh₃)₂Cl₂, Pd(OAc)₂,NiCl₂(dppe), Pd(OAc)₂, Pd₂(dba)₃, Cu(OAc)₂, CuI or the like may beemployed, typically along with a suitable base such as K₂CO₃, K₃PO₄,Cs₂CO₃, Et₃N, pyridine or the like. Additionally, ligands such as BINAP,di-tert-butyl phosphinobiphenyl, di-cyclohexylphosphino biphenyl, tritert-butylphosphine, XANTPHOS, triphenylarsine and the like may beadded. The reaction is carried out in a suitable solvent such astoluene, DME, dioxane, THF, water or a combination of the above and istypically heated at 50° C.-150° C. for between 1 and 48 hrs. Thereaction may be homogeneous or heterogeneous (see for example Miyaura,N.; Suzuki, A. Chem. Rev. 1995, 95, 2457-2483 and Dai, C.; Fu, G. C J.Am. Chem. Soc., 2001, 123, 2719-2724 and Littke, A. F.; Fu, G. C. Angew.Chem. Int. Ed. 1999, 38, 6, 2411-2413 and Dai, C; Fu, G. C. J. Am. Chem.Soc. 2001,123, 2719-2724).

Alternatively ring systems W or Z may be a nitrogen containingheterocycle wherein the nitrogen is directly attached to the ring systemX or Y respectively. In this case G and/or J are groups capable ofundergoing a metal catalyzed N-aryl cross-coupling (such as halogen,trifluoromethane-sulfonate, B(OR)₂, ZnX, SnR₃, and the like—Scheme 6).Typically a transition metal such as CuI, Cu(OAc)₂, Cu(OTf)₂, Pd(PPh₃)₄,Pd(PPh₃)₂Cl₂, Pd(OAc)₂, Pd₂(dba)₃, NiCl₂(dppe) is used along with asuitable base such as as K₂CO₃, K₃PO₄, Cs₂CO₃, NaOtBu or the like.Additionally, phosphine containing ligands such as BINAP, di-tert-butylphosphinobiphenyl, di-cyclohexylphosphino biphenyl, tritert-butylphosphine, XANTPHOS and the like may be added. Further,additives such as 1,10-phenanthroline, 1,2-diaminocyclohexane,dibenzylideneacetone may be used. The reaction is typically carried outin a solvent such as toluene, DME, dioxane, THF, water or a combinationof the above and is typically heated at 50° C. -150° C. for between 1and 48 hrs. The reaction may be homogeneous or heterogeneous. Theproduct from Scheme 6, can be isolated and purified employing standardtechniques, such as solvent extraction, acid-base extraction,chromatography, crystallization, distillation and the like (see forexample Lam, P. Y. S.; Clark, C. G.; Saubern, S.; Adams, J.; Winters, M.P.; Cham, D. M. T.; Combs, A. Tetrahedron Lett. 1998, 39, 2941-2944 andKiyomori, A.; Marcoux, J. F.; Buchwald, S. L. Tetrahedron Lett. 1999,40,2657-2660 and Wolfe, J. P.; Tomori, H.; Sadighi, J. P.; Yin, J.;Buchwald, S. L J. Org. Chem., 2000, 65, 1158-1174 and Yin, J.; Buchwald,S. L.; Org. Lett., 2000, 2, 1101-1104).

In addition, many of the heterocyclic compounds described above can beprepared using other synthetic chemistry techniques well known in theart (see Comprehensive Heterocyclic Chemistry, Katritzky, A. R. andRees, C. W. eds., Pergamon Press, Oxford, 1984) and references citedthere within.

COMPOUND 1 Synthesis of 4-(4-bromophenyl)-1H-imidazole

A solution of 4-bromophenylacyl bromide (2.5 g, 9 mmol) in formamide (45mL) was heated to 190° C. for 2 h. The reaction mixture was allowed tocool to room temperature and then poured into water (200 mL). Theresulting mixture was extracted with dichloromethane (100 mL) and washedwith water and brine. The organic layer was dried over Na₂SO₄, filtered,and concentrated in vacuo. ¹H-NMR (CD₃OD, 500 MHz): δ 7.75 (s, 1H),7.66-7.64 (m, 2H), 7.53-7.49 (m, 3H).

COMPOUND 2 Synthesis of 2-[4-(4-bromophenyl)-1H-imidazol-1-yl]pyridine

To a solution of compound 1 (0.9 g, 4.0 mmol) in DMF (4.0 mL) was added2-bromopyridine (0.4 mL, 4.0 mmol) and potassium carbonate (1.7 g, 12.0mmol). The resulting suspension was heated to 170-180° C. for 12 h. Thereaction mixture was allowed to cool to room temperature, diluted withEtOAc (100 mL), and washed with water and brine. The organic layer wasdried over Na₂SO₄, filtered, and concentrated in vacuo. The cruderesidue was purified by silica gel chromatography, eluting with 50-80%EtOAc/hexane, to afford 2-[4-(4-bromophenyl)-1H-imidazol-1-yl]pyridineas brown solid. ¹H-NMR (CDCl₃, 500 MHz): δ 8 8.54-8.53 (d, 1H), 8.39 (s,1H), 7.99 (s, 1H), 7.90-7.87 (m, 1H), 7.77-7.76 (m, 2H), 7.56-7.55 (m,2H), 7.45-7.43 (m, 1H), 7.31-7.38 (m, 1H). MS (ESI) 300.0 (M⁺).

EXAMPLE 1 Synthesis of2-[4-(4-pyridin-3-ylphenyl)-1H-imidazol-1-yl]pyridine

To a solution of compound 2 (580 mg, 1.9 mmol) in dioxane (12.8 mL) wasadded pyridine-3-boronic acid (470 mg, 3.8 mmol), potassium phosphate(810 mg, 3.8 mmol), palladium acetate (43 mg, 0.2 mmol), and1,1′-bis(diphenylphosphino)ferrocene (160 mg, 0.3 mmol). The reactionflask was sealed and the reaction mixture was heated to 110° C. for 12h. The reaction mixture was allowed to cool to room temperature and thenquenched by dilution with EtOAc (100 mL) and filtered over a cake ofCelite. The filtrate was washed with water and brine, dried over Na₂SO₄,filtered, and-concentrated in vacuo. The crude residue was purified bysilica gel chromatography, eluting with 0-10% MeOH/EtOAc, to afford2-[4-(4-pyridin-3-ylphenyl)-1H-imidazol-1-yl]pyridine. ¹H-NMR (CD₃OD,500 MHz): 8.83 (s, 1H), 8.60 (s, 1H) 8.51-8.50 (d, 2H), 8.29 (s, 1H),8.10 (m, 1H), 7.97-7.93 (m, 3H), 7.74-7.69 (m, 3H), 7.52-7.50 (m, 1H),7.38-7.35 (m, 1H). MS 299.1 (M⁺+H).

COMPOUND 3 Synthesis of 2-(1H-imidazol-4-yl)pyridine

2-(1H-Imidazol-4-yl)pyridine was prepared according to the method ofWang, F.; Schwabacher, A. W. Tetrahedron. Lett. 1999,40,4779-4782.

COMPOUND 4 Synthesis of2-[1-(3-bromo-5-methylphenyl)-1H-imidazol-4-yl]pyridine

To a solution of compound 3 (1.4 g, 9.5 mmol) in DMF (4.8 mL) was added3,5-dibromotoluene (3.8 g, 15.2 mmol), copper iodide (181 mg, 1.0 mmol),1,10-phenanthroline. (343 mg, 1.9 mmol), and cesium carbonate (6.5 g, 20mmol). The resulting mixture was heated to 110° C. for 16 h. Thereaction mixture was allowed to cool to room temperature, diluted withEtOAc (100 mL) and filtered over a cake of Celite. The filtrate waswashed with water and brine. The organic layer was dried over Na₂SO₄,filtered, and concentrated in vacuo. The crude residue was purified bysilica gel chromatography, eluting with 50% MeOH/EtOAc, to afford2-[1-(3-bromo-5-methylphenyl)-1H-imidazol-4-yl]pyridine. ¹H-NMR (CDCl₃,500 MHz): δ 8.60-8.59 (m, 1H), 8.06-8.03 (m, 2H), 7.91 (s, 1H),7.80-7.77 (m, 1H), 7.48 (s, 1H), 7.38 (s, 1H), 7.22 (s, 1H), 7.21-7.20(m, 1H). MS (ESI) 314.1 (M⁺).

EXAMPLE 2 Synthesis of2-[1-(3-methyl-5-pyridin-3-ylphenyl)-1H-imidazol-4-yl]pyridine

Compound 4 (0.36 g, 1.2 mmol), pyridine-3-boronic acid (281 mg, 2.3mmol), potassium phosphate (486 mg, 2.3 mmol), palladium acetate (27 mg,0.1 mmol), and dppf (94 mg, 0.2 mmol) were combined in dioxane (7.7 mL)and heated to 110° C. for 48 h. The reaction mixture was allowed to coolto room temperature, diluted with EtOAc (100 mL) and filtered over acake of Celite. The filtrate was washed with water and brine. Theorganic layer was dried over Na₂SO₄, filtered, and concentrated invacuo. The crude residue was purified by silica gel chromatography,eluting with 50-80% MeOH/EtOAc, to afford2-[1-(3-methyl-5-pyridin-3-ylphenyl)-1H-imidazol-4-yl]pyridine. ¹H-NMR(CD₃OD, 500 MHz): 8.92-8.91 (d, 1H), 8.66-8.65 (m, 1H), 8.60-8.58 (m,1H), 8.41 (m, 2H), 8.23-8.21 (m, 1H), 8.00-7.94 (m, 2H), 7.76 (s, 1H),7.62-7.57(m, 3H), 7.37(m, 1H), 2.56 (s, 3H). MS: 313.1 (M⁺+H).

EXAMPLE 3 to EXAMPLE 6

shown below were prepared similarly to the schemes and proceduresdescribed above. EXAMPLE Structure ¹H NMR MS (ESI) 3

8.92-8.90(m, 1H), 8.67(s, 1H), 8.56-8.55(m, 1H), 8.47(s, 1H), 8.22(m,1H), 8.11(s, 1H), 8.04-8.01(m, 1H), 7.96-7.91(d, 1H), 7.88-7.87(d, 1H),7.82-7.80(d, 1H), 7.75-7.74(m, 1H), 7.71-7.68(m, 1H), 7.58-7.56(m, 1H),7.44-7.41(m, 1H), 6.85-6.84(d, 1H). MS 338.1 (M + H)⁺. 4

8.99(s, 1H), 8.68(s, 1H), 8.66(s, 1H), 8.62-8.61(m, 1H), 8.56-8.55(m,1H), 8.25(s, 1H), 8.18-8.16(m, 1H), 8.09-8.06(m, 1H), 7.98-7.96(m, 1H),7.89-7.88(m, 1H), 7.65-7.63(m, 1H), 7.57-7.51(m, 2H), 7.44-7.41(m, 1H)MS 299.1 (M + H)⁺. 5

9.58(br, 1H), 8.95-8.94(m, 1H), 8.61-8.58(m, 1H), 8.47(m, 1H),8.29-8.27(br m, 2H), 8.04-8.02(m, 2H), 7.97-7.94(m, 1H), 7.78-7.77(m,1H), 7.72-7.70(m, 1H), 7.60-7.58(m, 1H), 7.46-7.43(m, 1H). MS 317.2 (M +H)⁺. 6

8.82-8.80(m, 2H), 8.41-8.39(m, 1H), 8.19-8.16(m, 1H), 8.14-8.13(d, 1H),7.84-7.83(m, 1H), 7.75-7.72(m, 1H), 7.63-7.62(m, 1H), 7.56-7.44(m, 5H).MS 337.2 (M + H)⁺.

Other variations or modifications, which will be obvious to thoseskilled in the art, are within the scope and teachings of thisinvention. This invention is not to be limited except as set forth inthe following claims.

1. A compound represented by Formula (I):

or a pharmaceutically acceptable salt thereof, wherein: X and Y eachindependently is aryl or heteroaryl wherein at least one of X and Y is aheteroaryl with N adjacent to the position of attachment to A or Brespectively; X is optionally substituted with 1-7 independent halogen,—CN, NO₂, —C₁₋₆alkyl, —C₁₋₆alkenyl, —C₁₋₆alkynyl, —OR¹, —NR¹R²,—C(═NR¹)NR²R³, —N(═NR¹)NR²R³, —NR¹COR², —NR¹CO₂R², —NR¹SO₂R⁴,—NR¹CONR²R³, —SR⁴, —SOR⁴, —SO₂R⁴, —SO₂NR¹R², —COR¹, —CO₂R¹, —CONR¹R²,—C(═NR¹)R², or —C(═NOR¹)R² substituents, wherein optionally twosubstituents are combined to form a cycloalkyl or heterocycloalkyl ringfused to X; wherein the —C₁₋₆alkyl substituent, cycloalkyl ring, orheterocycloalkyl ring each optionally is further substituted with 1-5independent halogen, —CN, —C₁₋₆alkyl, —O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl),—O(aryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl), —N(C₀₋₆alkyl)(C₃₋₇cycloalkyl), or—N(C₀₋₆alkyl)(aryl) groups; R¹, R², and R³ each independently is—C₀₋₆alkyl, —C₃₋₇cycloalkyl, heteroaryl, or aryl; any of which isoptionally substituted with 1-5 independent halogen, —CN, —C₁₋₆alkyl,—O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl), —O(aryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl),—N(C₀₋₆alkyl)(C₃₋₇cycloalkyl), —N(C₀₋₆alkyl)(aryl) substituents; R⁴ is—C₁₋₆alkyl, —C₃₋₇cycloalkyl, heteroaryl, or aryl; optionally substitutedwith 1-5 independent halogen, —CN, —C₁₋₆alkyl, —O(C₀₋₆alkyl),—O(C₃₋₇cycloalkyl), —O(aryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl),—N(C₀₋₆alkyl)(C₃₋₇cycloalkyl), —N(C₀₋₆alkyl)(aryl) substituents; A is—C₀₋₄alkyl, —C₀₋₂alkyl-SO—C₀₋₂alkyl-, —C₀₋₂alkyl-SO₂—C₀₋₂alkyl-,—C₀₋₂alkyl-CO—C₀₋₂alkyl-, —C₀₋₂alkyl-NR⁹CO—C₀₋₂alkyl-,—C₀₋₂alkyl-NR⁹SO₂—C₀₋₂alkyl- or —heteroC₀₋₄alkyl; W is —C₃₋₇cycloalkyl,-heteroC₃₋₇cycloalkyl, —C₀₋₆alkylaryl, or —C₀₋₆alkylheteroaryloptionally substituted with 1-7 independent halogen, —CN, NO₂,—C₁₋₆alkyl, —C₁₋₆alkenyl, —C₁₋₆alkynyl, —OR¹, —NR¹R², —C(═NR¹)NR²R³,—N(═NR¹)NR²R³, —NR¹COR², —NR¹CO₂R², —NR¹SO₂R⁴, —NR¹CONR²R³, —SR⁴, —SOR⁴,—SO₂R⁴, —SO₂NR¹R², —COR¹, —CO₂R¹, —CONR¹R², —C(═NR¹)R², or —C(═NOR¹)R²substituents; Y is optionally substituted with 1-7 independent halogen,—CN, NO₂, —C₁₋₆alkyl, —C₁₋₆alkenyl, —C₆alkynyl, —OR⁵, —NR⁵R⁶,—C(═NR⁵)NR⁶R⁷, —N(═NR⁵)NR⁶R⁷, —NR⁵COR⁶, —NR⁵CO₂R⁶, —NR⁵SO₂R⁸,—NR⁵CONR⁶R⁷, —SR⁸, —SOR⁸, —SO₂R⁸, —SO₂NR⁵R⁶, —COR⁵, —CO₂R⁵, —CONR⁵R⁶,—C(═NR⁵)R⁶, or —C(═NOR⁵)R⁶ substituents, wherein optionally twosubstituents are combined to form a cycloalkyl or heterocycloalkyl ringfused to Y; wherein the —C₁₋₆alkyl substituent, cycloalkyl ring, orheterocycloalkyl ring each optionally is further substituted with 1-5independent halogen, —CN, —C₁₋₆alkyl, —O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl),—O(aryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl), —N(C₀₋₆alkyl)(C₃₋₇cycloalkyl), or—N(C₀₋₆alkyl)(aryl) groups; R⁵, R⁶, and R⁷ each independently is—C₀₋₆alkyl, —C₃₋₇cycloalkyl, heteroaryl, or aryl; any of which isoptionally substituted with 1-5 independent halogen, —CN, —C₁₋₆alkyl,—O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl), —O(aryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl),—N(C₀₋₆alkyl)(C₃₋₇cycloalkyl), —N(C₀₋₆alkyl)(aryl) substituents; R⁸ is—C₁₋₆alkyl, —C₃₋₇cycloalkyl, heteroaryl, or aryl; optionally substitutedwith 1-5 independent halogen, —CN, —C₁₋₆alkyl, —O(C₀₋₆alkyl),—O(C₃₋₇cycloalkyl), —O(aryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl),—N(C₀₋₆alkyl)(C₃₋₇cycloalkyl), —N(C₀₋₆alkyl)(aryl) substituents; B is—C₀₋₄alkyl, —C₀₋₂alkyl-SO—C₀₋₂alkyl-, —C₀₋₂alkyl-SO₂—C₀₋₂alkyl-,—C₀₋₂alkyl-CO—C₀₋₂alkyl-, —C₀₋₂alkyl-NR¹⁰CO—C₀₋₂alkyl-,—C₀₋₂alkyl-NR¹⁰SO₂—C₀₋₂alkyl- or -heteroC₀₋₄alkyl; R⁹ and R¹⁰ eachindependently is —C₀₋₆alkyl, —C₃₋₇cycloalkyl, heteroaryl, or aryl; anyof which is optionally substituted with 1-5 independent halogen, —CN,—C₁₋₆alkyl, —O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl), —O(aryl),—N(C₀₋₆alkyl)(C₀₋₆alkyl), —N(C₀₋₆alkyl)(C₃₋₇cycloalkyl),—N(C₀₋₆alkyl)(aryl) substituents; Z is —C₃₋₇cycloalkyl,-heteroC₃₋₇cycloalkyl, —C₀₋₆alkylaryl, or —C₀₋₆alkylheteroaryloptionally substituted with 1-7 independent halogen, —CN, NO₂,—C₁₋₆alkyl, —C₁₆alkenyl, —C₁₋₆alkynyl, —OR¹, —NR¹R², —C(═NR¹)NR²R³,—N(═NR¹)NR²R³, —NR¹COR², —NR¹CO₂R², —NR¹SO₂R⁴, —NR¹CONR²R³, —SR⁴, —SOR⁴,—SO₂R⁴, —SO₂NR¹R², —COR¹, —CO₂R¹, —CONR¹R², —C(═NR¹)R², or —C(═NOR¹)R²substituents; one of W and Z is optionally absent; R¹¹ and R¹² is eachindependently halogen, —C₀₋₆alkyl, —C₀₋₆alkoxyl, ═O, ═N(C₀₋₄alkyl),or—N(C₀₋₄alkyl)(C₀₋₄alkyl); and any alkyl optionally substituted with 1-5independent halogen substituents, and any N may be an N-oxide.
 2. Thecompound according to claim 1, or a pharmaceutically acceptable saltthereof, wherein: X is 2-pyridyl optionally substituted with 1-4independent halogen, —CN, NO₂, —C₁₋₆alkyl, —C₁₋₆alkenyl, —C₁₋₆alkynyl,—OR¹, —NR¹R², —C(═NR¹)NR²R³, —N(═NR¹)NR²R³, —NR¹COR², —NR¹CO₂R²,—NR¹SO₂R⁴, —NR¹CONR²R³, —SR⁴, —SOR⁴, —SO₂R⁴, —SO₂NR¹R², —COR¹, —CO₂R¹,—CONR¹R², —C(═NR¹)R², or —C(═NOR¹)R² substituents, wherein twosubstituents are combined to form a cycloalkyl or heterocycloalkyl ringfused to X; wherein the —C₁₋₆alkyl substituent, cycloalkyl ring, orheterocycloalkyl ring each optionally is further substituted with 1-5independent halogen, —CN, —C₁₋₆alkyl, —O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl),—O(aryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl), —N(C₀₋₆alkyl)(C₃₋₇cycloalkyl), or—N(C₀₋₆alkyl)(aryl) groups.
 3. The compound according to claim 2, or apharmaceutically acceptable salt thereof, wherein: Y is phenyloptionally substituted with 1-5 independent halogen, —CN, NO₂,—C₁₋₆alkyl, —C₁₋₆alkenyl, —C₁₋₆alkynyl, —OR⁵, —NR⁵R⁶, —C(═NR⁵)NR⁶R⁷,—NR⁵COR⁶, —NR⁵CO₂R⁶, —NR⁵SO₂R⁸, —NR⁵CONR⁶R⁷, —SR⁸, —SOR⁸, —SO₂R⁸,—SO₂NR⁵R⁶, —COR⁵, —CO₂R⁵, —CONR⁵R⁶, —C(═NR⁵)R⁶, or —C(═NOR⁵)R⁶substituents, wherein optionally two substituents are combined to form acycloalkyl or heterocycloalkyl ring fused to Y; wherein the —C₁₋₆alkylsubstituent, cycloalkyl ring, or heterocycloalkyl ring each optionallyis further substituted with 1-5 independent halogen, —CN, —C₁₋₆alkyl,—O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl), —O(aryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl),—N(C₀₋₆alkyl)(C₃₋₇cycloalkyl), or —N(C₀₋₆alkyl)(aryl) groups.
 4. Thecompound according to claim 1, or a pharmaceutically acceptable saltthereof, wherein: Y is 2-pyridyl optionally substituted with 1-4independent halogen, —CN, NO₂, —C₁₋₆alkyl, —C₁₋₆alkenyl, —C₁₋₆alkynyl,—OR⁵, —NR⁵R⁶, —C(═NR⁵)NR⁶R⁷, —NR⁵COR⁶, —NR⁵CO₂R⁶, —NR⁵SO₂R⁸,—NR⁵CONR⁶R⁷, —SR⁸, —SOR⁸, —SO₂R⁸, —SO₂NR⁵R⁶, —COR⁵, —CO₂R⁵, —CONR⁵R⁶,—C(═NR⁵)R⁶, or —C(═NOR⁵)R⁶ substituents, wherein optionally twosubstituents are combined to form a cycloalkyl or heterocycloalkyl ringfused to Y; wherein the —C₁₋₆alkyl substituent, cycloalkyl ring, orheterocycloalkyl ring each optionally is further substituted with 1-5independent halogen, —CN, —C₁₋₆alkyl, —O(C₀₋₆alkyl), -O(C₃₋₇cycloalkyl),—O(aryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl), —N(C₀₋₆alkyl)(C₃₋₇cycloalkyl), or—N(C₀₋₆alkyl)(aryl) groups.
 5. The compound according to claim 4, or apharmaceutically acceptable salt thereof, wherein: X is phenyloptionally substituted with 1-5 independent halogen, —CN, NO₂,—C₁₋₆alkyl, —C₁₋₆alkenyl, —C₁₋₆alkynyl, —OR¹, —NR¹R², —C(═NR¹)NR²R³,—N(═NR¹)NR²R³, —NR¹COR², —NR¹CO₂R², —NR¹SO₂R⁴, —NR¹CONR²R³, —SR⁴, —SOR⁴,—SO₂R⁴, —SO₂NR¹R², —COR¹, —CO₂R¹, —CONR¹R², —C(═NR¹)R², or —C(═NOR¹)R²substituents, wherein optionally two substituents are combined to form acycloalkyl or heterocycloalkyl ring fused to X; wherein the —C₁₋₆alkylsubstituent, cycloalkyl ring, or heterocycloalkyl ring each optionallyis further substituted with 1-5 independent halogen, —CN, —C₁₋₆alkyl,—O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl), —O(aryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl),—N(C₀₋₆alkyl)(C₃₋₇cycloalkyl), or —N(C₀₋₆alkyl)(aryl) groups.
 6. Thecompound according to claim 1, or a pharmaceutically acceptable saltthereof, wherein: X is phenyl optionally substituted with 1-5independent halogen, —CN, NO₂, —C₁₋₆alkyl, —C₁₋₆alkenyl, —C₁₋₆alkynyl,—OR⁵, —NR⁵R⁶, —C(═NR⁵)NR⁶R⁷, —N(═NR⁵)NR⁶R⁷, —NR⁵COR⁶, —NR⁵CO₂R⁶,—NR⁵SO₂R⁸, —NR⁵CONR⁶R⁷, —SR⁸, —SOR⁸, —SO₂R⁸, —SO₂NR⁵R⁶, —COR⁵, —CO₂R⁵,—CONR⁵R⁶, —C(═NR⁵)R⁶, or —C(═NOR⁵)R⁶ substituents, wherein optionallytwo substituents are combined to form a cycloalkyl or heterocycloalkylring fused to Y; wherein the —C₁₋₆alkyl substituent, cycloalkyl ring, orheterocycloalkyl ring each optionally is further substituted with 1-5independent halogen, —CN, —C₁₋₆alkyl, —O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl),—O(aryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl), —N(C₀₋₆alkyl)(C₃₋₇cycloalkyl), or—N(C₀₋₆alkyl)(aryl) groups.
 7. The compound according to claim 1, or apharmaceutically acceptable salt thereof, wherein: Y is phenyloptionally substituted with 1-5 independent halogen, —CN, NO₂,—C₁₋₆alkyl, —C₁₋₆alkenyl, —C₁₋₆alkynyl, —OR⁵, —NR⁵R⁶, —C(═NR⁵)NR⁶R⁷,—N(═NR⁵)NR⁶R⁷, —NR⁵COR⁶, —NR⁵CO₂R⁶, —NR⁵SO₂R⁸, —NR⁵CONR⁶R⁷, —SR⁸, —SOR⁸,—SO₂R⁸, —SO₂NR⁵R⁶, —COR⁵, —CO₂R⁵, —CONR⁵R⁶, —C(═NR⁵)R⁶, or —C(═NOR⁵)R⁶substituents, wherein optionally two substituents are combined to form acycloalkyl or heterocycloalkyl ring fused to Y; wherein the —C₁₋₆alkylsubstituent, cycloalkyl ring, or heterocycloalkyl ring each optionallyis further substituted with 1-5 independent halogen, —CN, —C₁₋₆alkyl,—O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl), —O(aryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl),—N(C₀₋₆alkyl)(C₃₋₇cycloalkyl), or —N(C₀₋₆alkyl)(aryl) groups.
 8. Thecompound according to claim 1, or a pharmaceutically acceptable saltthereof, wherein: Z is —C₀₋₆alkylaryl, or —C₀₋₆alkylheteroaryloptionally substituted with 1-7 independent halogen, —CN, NO₂,—C₁₋₆alkyl, —C₁₋₆alkenyl, —C₁₋₆alkynyl, —OR¹, —NR¹R², —C(═NR¹)NR²R³,—N(═NR¹)NR²R³, —NR¹COR², —NR¹CO₂R², —NR¹SO₂R⁴, —NR¹CONR²R³, —SR⁴, —SOR⁴,—SO₂R⁴, —SO₂NR¹R², —COR¹, —CO₂R¹, —CONR¹R², —C(═NR¹)R², or −C(═NOR¹)R²substituents.
 9. The compound according to claim 1, or apharmaceutically acceptable salt thereof, wherein: W is —C₀₋₆alkylaryl,or —C₀₋₆alkylheteroaryl optionally substituted with 1-7 independenthalogen, —CN, NO₂, C₁₋₆alkyl, —C₁₋₆alkenyl, —C₁₋₆alkynyl, —OR¹, —NR¹R²,—C(═NR ¹)NR²R³, —N(═NR ¹)NR²R³, —NR¹COR², —NR¹CO₂R², —NR¹SO₂R⁴,—NR¹CONR²R³, —SR⁴, —SOR⁴, —SO₂R⁴, —SO₂NR¹R², —COR¹, —CO₂R¹, —CONR¹R²,—C(═NR¹)R², or —C(═NOR¹)R² substituents.
 10. The compound according toclaim 3, or a pharmaceutically acceptable salt thereof, wherein: Z is—C₀₋₆alkylaryl, or —C₀₋₆alkylheteroaryl optionally substituted with 1-7independent halogen, —CN, NO₂, —C₁₋₆alkyl, —C₁₋₆alkenyl, —C₁₋₆alkynyl,—OR¹, —NR¹R², —C(═NR¹)NR²R³, —N(═NR¹)NR²R³, —NR¹COR², —NR¹CO₂R²,—NR¹SO₂R⁴, —NR¹CONR²R³, —SR⁴, —SOR⁴, —SO₂R⁴, —SO₂NR¹R², —COR¹, —CO₂R¹,—CONR¹R², —C(═NR¹)R², or —C(═NOR¹)R² substituents.
 11. The compoundaccording to claim 5, or a pharmaceutically acceptable salt thereof,wherein: W is —C₀₋₆alkylaryl, or —C₀₋₆alkylheteroaryl optionallysubstituted with 1-7 independent halogen, —CN, NO₂, —C₁₋₆alkyl,—C₁₋₆alkenyl, —C₁₋₆alkynyl, —OR¹, —NR¹R², —C(═NR¹)NR²R³, —N(═NR¹)NR²R³,—NR¹COR², —NR¹CO₂R², —NR¹SO₂R⁴, —NR¹CONR²R³, —SR⁴, —SOR⁴, —SO₂R⁴,—SO₂NR¹R², —COR¹, —CO₂R¹, —CONR¹R², —C(═NR¹)R², or —C(═NOR¹)R²substituents.
 12. The compound according to claim 1, consisting of:2-[4-(4-pyridin-3-ylphenyl)-1H-imidazol-1-yl]pyridine;1-[3-(1-pyridin-2-yl-1H-imidazol-4-yl)phenyl]-1H-pyrrolo[2,3-c]pyridine;2-[4-(3-pyridin-3-ylphenyl)-1H-imidazol-1-yl]pyridine;2-[2-fluoro4-(4-pyridin-2-yl-1H-imidazol-1-yl)phenyl]pyridine;2-[1-(3-methyl-5-pyridin-3-ylphenyl)-1H-imidazol-4-yl]pyridine;3′-methyl-5′-(4-pyridin-2-yl-1H-imidazol-1-yl)-1,1′-biphenyl-2-carbonitrileor a pharmaceutically acceptable salt thereof.
 13. The compoundaccording to claim 1, selected from:

or a pharmaceutically acceptable salt thereof.
 14. A pharmaceuticalcomposition comprising: a therapeutically effective amount of thecompound according to claim 1, or a pharmaceutically acceptable saltthereof; and a pharmaceutically acceptable carrier.
 15. Thepharmaceutical composition according to claim 14, further comprising i)an opiate agonist, ii) an opiate antagonist, iii) a calcium channelantagonist, iv) a 5HT receptor agonist, v) a 5HT receptor antagonist,vi) a sodium channel antagonist, vii) an NMDA receptor agonist, viii) anNMDA receptor antagonist, ix) a COX-2 selective inhibitor, x) an NK1antagonist, xi) a non-steroidal anti-inflammatory drug, xii) a GABA-Areceptor modulator, xiii) a dopamine agonist, xiv) a dopamineantagonist, xv) a selective serotonin reuptake inhibitor, xvi) atricyclic antidepressant drug, xvii) a norepinephrine modulator, xviii)L-DOPA, xix) buspirone, xx) a lithium salt, xxi) valproate, xxii)neurontin, xxiii) olanzapine, xxiv) a nicotinic agonist, xxv) anicotinic antagonist, xxvi) a muscarinic agonist, xxvii) a muscarinicantagonist, xxviii) a selective serotonin and norepinephrine reuptakeinhibitor (SSNRI), xxix) a heroin substituting drug, xxx) disulfiram, orxxxi) acamprosate.
 16. The pharmaceutical composition according to claim15, wherein said heroin substituting drug is methadone,levo-alpha-acetylmethadol, buprenorphine or naltrexone.
 17. The use ofthe compound of claim 1 for the preparation of a medicament useful inthe treatment of pain disorders, extrapyramidal motor functiondisorders, anxiety disorders, Parkinson's disease, depression, epilepsy,cognitive disfunction, drug addiction, circadian rhythm and sleepdisorders, and obesity.
 18. The use according to claim 17 wherein saidpain disorder is acute pain, persistent pain, chronic pain, inflammatorypain, or neuropathic pain.
 19. The use of the compound of claim 1 forthe preparation of a medicament useful in the treatment of anxiety,depression, bipolar disorder, psychosis, drug withdrawal, tobaccowithdrawal, memory loss, cognitive impairment, dementia, Alzheimer'sdisease, schizophrenia or panic.
 20. The use according to claim 17wherein said disorder of extrapyramidal motor function is Parkinson'sdisease, progressive supramuscular palsy, Huntington's disease, Gillesde la Tourette syndrome, or tardive dyskinesia.